A facile one-pot expeditious synthesis of thiazolyl-pyrazolones

Article abstract of DOI:10.1080/10426507.2010.505593

A novel, one-pot, multicomponent synthesis of 4-arylidene-3-methyl-1-(4- arylthiazol-2-yl)-1H-pyrazol-5(4H)-ones is described using phenacyl bromides, thiosemicarbazide, ethylacetoacetate, and aryl aldehydes. This synthesis involves simultaneous formation

Full text of DOI:10.1080/10426507.2010.505593

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Phosphorus, Sulfur, and Silicon and the
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A Facile One-Pot Expeditious Synthesis of
Thiazolyl-pyrazolones
Chunduru S. R. Venkata a & Vedula Rajeswar Rao a
a Department of Chemistry, National Institute of Technology,
Warangal, India
Published online: 07 Mar 2011.
To cite this article: Chunduru S. R. Venkata & Vedula Rajeswar Rao (2011) A Facile One-Pot
Expeditious Synthesis of Thiazolyl-pyrazolones, Phosphorus, Sulfur, and Silicon and the Related
Elements, 186:3, 489-495, DOI: 10.1080/10426507.2010.505593
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Phosphorus, Sulfur, and Silicon, 186:489–495, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.505593
A FACILE ONE-POT EXPEDITIOUS SYNTHESIS
OF THIAZOLYL-PYRAZOLONES
Chunduru S. R. Venkata and Vedula Rajeswar Rao
Department of Chemistry, National Institute of Technology, Warangal, India
GRAPHICAL ABSTRACT
R
S
NH2
+
H2N
N
Br
H
R
O
CH3
2
1
N
N
AcOH/AcONa
N
H
CHO
∆
R1
R2
S
R1
R2
O
O
O
+
5
OEt
R4
R4
R3
R3
4
3
Abstract A novel, one-pot, multicomponent synthesis of 4-arylidene-3-methyl-1-(4-
arylthiazol-2-yl)-1H-pyrazol-5(4H)-ones is described using phenacyl bromides, thiosemicar-
bazide, ethylacetoacetate, and aryl aldehydes. This synthesis involves simultaneous formation
of two heterocycles like thiazole and pyrazolone along with condensation of active methylene
group by aldehydes via Knoevenagel reaction. The methodology is mild, efficient, and high
yielding.
Keywords Knoevenagel reaction; one pot reaction; phenacyl bromide; pyrazolone; thiazole
INTRODUCTION
Sulfur and nitrogen heterocycles having pharmaceutical activities are widely occur-
ring in nature in the form of alkaloids, vitamins, pigments, and as constituents of plant and
animal cells. Penicillins containing a thiazole ring system (thiazolidine)1 are also important
naturally occurring products. Thiazoles and their derivatives are found to possess various
biological activities such as antituberculosis2 and anti-HIV.3,4 On the other hand, pyrazole
derivatives have been reported in the literature to exhibit various pharmacological activities
such as anti-inflammatory,5 antihypertensive,6 and antimicrobial.7–9
Currently, multicomponent reactions (MCRs) play an important role in combinatorial
chemistry because of their ability to synthesize small drug-like molecules with several
Received 11 May 2010; accepted 28 June 2010.
The authors are thankful to the Director, National Institute of Technology, Warangal, for providing facilities.
One of the authors (CHVSR) is thankful to the Director for awarding Institute Fellowship.
Address correspondence to Vedula Rajeswar Rao, Department of Chemistry, National Institute of Technol-
ogy, Warangal-506 004, A.P., India. E-mail: vrajesw@yahoo.com
489

490
C. S. R. VENKATA AND V. RAJESWAR RAO
degrees of structural diversity. In the MCR, three or more different starting materials react
to form a product, where most, if not all, of the atoms are incorporated in the final product.
This reaction tool allows compounds to be synthesized in a few steps and usually in a one-
pot operation.10–13 Another typical benefit from these reactions is simplified purification,
because all of the reagents are incorporated into the final product.
In view of the pharmacological and biochemical properties and therapeutic applica-
tions of substituted thiazoles and pyrazoles, we became interested in an efficient preparation
of thiazolyl-pyrazolone derivatives via one-pot, multicomponent reaction. The methodol-
ogy was particularly interesting for us because thiazolyl-pyrazole derivatives also known
to possess a wide range of medicinal applications such as antimicrobial,14 antiviral,15 an-
tiamoebic,16 and herbicidal activity.17 Given this proven utility, it seems reasonable that
the development of libraries of substituted thiazolyl-pyrazolone derivatives might provide
additional lead molecules for use in drug discovery.
RESULTS AND DISCUSSION
In connection with our research program directed toward the synthesis of novel
heterocyclic systems,18–20 we report in this article the Hantzsch-thiazole synthesis and
concomitant formation of thiazolyl-pyrazolone along with condensation of aldehyde moiety
on active methylene group of pyrazolone under Knoevenagel reaction conditions. This a
four-component reaction (Scheme 1). The procedure involves heating an equimolar mixture
of phenacyl bromides, thiosemicarbazide, ethyl acetoacetate, and aldehyde in acetic acid
using sodium acetate as a base. In the literature, it has been reported that the synthesis of the
title compounds requires a multistep process.21 The first step involves in the preparation of
N-acetyl thiosemicarbazide. This upon reaction with various phenacyl bromides gives the
corresponding 2-N-acetyl hydrazine-4-phenylthiazoles. These are deacetylated to yield the
corresponding 2-hydrazino-4-phenylthiazoles, which on reaction with ethyl acetoacetate
lead to the formation of the polycyclic ring system. Though the above methodologies are
quite useful, they have some limitations, such as the need of the isolation of intermediates,
longer reactions times, application of harsh chemicals, and the overall yields are lower.
R
S
NH2
+
H2N
N
Br
H
R
O
CH3
2
1
N
N
N
AcOH/AcONa
H
CHO
∆
R1
R2
S
R1
R2
O
O
O
+
5
OEt
R4
R4
R3
R3
3
4
Scheme 1 Synthesis of 4-arylidene-3-methyl-1-(4-arylthiazol-2-yl)-1H-pyrazol-5(4H)-ones.
It is thus evident that there remains scope for the development of clean and efficient
methodologies involving single-step reactions for the preparation of the above said com-
pounds. We have developed a one-pot synthesis of these compounds in good yields (Table 1)
when compared to alternative available procedures. The condensation of phenacyl bro-
mides with thiosemicarbazide, ethyl acetoacetate, and aldehyde in acetic acid using sodium

ONE-POT SYNTHESIS OF THIAZOLYL-PYRAZOLONES
491
Table 1 Synthesis of 4-arylidene-3-methyl-1-(4-arylthiazol-2-yl)-1H-pyrazol-5(4H)-ones 5a
Product
R
R1
R2
R3
R4
Yield (%)b
Mp (◦C)
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
H
H
H
H
H
H
H
H
H
H
H
Br
H
H
H
Br
N(CH3)2
N(CH3)2
CH3
OCH3
Cl
H
H
H
H
H
H
H
H
75
79
74
75
73
81
83
83
80
78
84
85
120–122
128–130
>300
220–222
244–246
228–230
>300
240–242
250–252
140–142
248–250
228–230
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
H
OH
OH
OH
OH
H
H
Br
Br
Cl
H
Br
Br
H
5j
5k
5l
N(CH3)2
H
H
OH
OH
aAll reactions were performed using 1a (1.0 mmol), 2a (1.0 mmol), 3a (1.0 mmol), and 4a aldehyde (1.2 mmol)
in acetic acid and sodium acetate under heating.
bIsolated yields.
acetate gave 4-arylidene-3-methyl-1-(4-arylthiazol-2-yl)-1H-pyrazol-5(4H)-ones 5. In this
reaction, the thiocarboxamide part of thiosemicarbazide reacts with phenacyl bromide to
give a Hantzsch-thiazole product,22,23 and the hydrazine part of thiosemicarbazide reacts
with ethyl acetoacetate to yield the pyrazolone24,25 moiety having an active methylene
group, and without isolation of the intermediate addition of sodium acetate and aryl alde-
hyde to the reaction mixture gave the Knoevenagel26,27 product 4-arylidene-3-methyl-1-
(4-arylthiazol-2-yl)-1H-pyrazol-5(4H)-one 5. In this reaction, sodium acetate generates a
carbanion, which undergoes nucleophilic addition followed by intramolecular dehydration
to give 5 in good yields. Isolation of the product is achieved by filtration followed by
washing with water and drying. This process is fairly general, quick, and efficient, and is
devoid of any side products.
The IR spectrum of compound 5a, 5b showed prominent peak at 1674 cm−1 for
1
–C O of pyrazolone. H NMR of compound 5a, 5b showed characteristic singlets for
CH3 of pyrazolone at δ 2.47 and N,N-dimethyl at δ 3.17 and 3.18. The 13 C NMR of 5a,
5b showed the peaks at δ 13.5 for CH3 of pyrazolone, δ 40.0 δ and δ 162.1 for C O of
pyrazolone. Similarly the IR spectrum of compound 5f showed prominent peaks at 1693
cm−1 for C O of pyrazolone, 3109 cm−1 for phenolic OH, 1H NMR of compound 5f
showed singlet for CH3 of pyrazolone at δ 2.48, δ 10.11 for phenolic OH. From all the
above spectral data, there is clearly evidence for the formation of products 4-arylidene-3-
methyl-1-(4-arylthiazol-2-yl)-1H-pyrazol-5(4H)-ones 5.
In conclusion, novel, facile, one-pot, multicomponent 4-arylidene-3-methyl-1-(4-
arylthiazol-2-yl)-1H-pyrazol-5(4H)-ones have been developed via a one-pot reaction. The
advantages of this methodology are mild reaction conditions, no catalyst requirement,
easy workup, clean reaction profile, shorter reaction time, and wide range of substrate
applicability.
EXPERIMENTAL
All the reagents and solvents were pure, purchased from commercial sources, and
were used without further purification unless otherwise stated. Melting points were deter-
mined in open capillaries with a “Cintex” melting point apparatus (Mumbai, India) and

492
C. S. R. VENKATA AND V. RAJESWAR RAO
were uncorrected. CHNS analysis was done by a Carlo Erba EA 1108 automatic elemental
analyzer. The purity of the compounds was checked by TLC plates (E. Merck, Mumbai,
India). IR spectra (KBr) were recorded on a Bruker WM-4(X) spectrometer (577 model).
1H NMR spectra were recorded on a Bruker WM-400 spectrometer in δ ppm using TMS
as standard. Mass spectra (EI-MS) were determined on Perkin Elmer (SCIEX API- 2000,
ESI) at 12.5 eV.
General Procedure for the Synthesis of 4-Arylidene-3-methyl-1-
(4-arylthiazol-2-yl)-1H-pyrazol-5(4H)-ones 5a–l
Phenacyl bromide (1 mmol), thiosemicarbazide (1 mmol), and ethylacetoacetate
(1 mmol) were taken in acetic acid (10 mL), heated at 50–55◦C for about 2 h. The reaction
mixture was cooled to rt, and then sodium acetate (2 mmol) and aryl aldehyde (1.2 mmol)
were added 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-(4-(Dimethylamino)benzylidene)-3-methyl-1-(4-phenylthiazol-
2-yl)-1H-pyrazol-5(4H)-one (5a)
Red solid; IR (KBr): υ 3076 ( C H, Ar-H), 1674 (C O, pyrazolone), 1618 (C N),
1552 (C C). 1H NMR (400 MHz, CDCl3): δ 2.44 (s, 3H, CH3 of pyrazolone), 3.17 (s, 6H,
N,N-dimetyl), 6.76 (d, 2H, J = 9.2Hz, ArH), 7.23–7.41 (m, 5H, 4H-ArH and 1H, Ar-CH ),
7.99 (d, 2H, 1H-ArH, 1H-thiazole), 8.56 (d, 2H, J = 9.2Hz, ArH). 13C NMR (CDCl3 δ
ppm): 13.5, 40.0, 107.1, 111.4, 117.4, 121.6, 126.4, 127.7, 128.3, 134.3, 137.8, 149.0,
150.8, 154.2, 154.3, 155.3 and 162.1. EI-MS 417 [M+39]+. Anal. calcd. for C22H20N4OS:
C, 68.02; H, 5.19; N, 14.42; Found: C, 68.00; H, 5.15; N, 14.48.
4-(4-(Dimethylamino)benzylidene)-1-(4-(4-chlorophenyl)thiazol-2-
yl)-3-methyl-1H-pyrazol-5(4H)-one (5b)
Red solid; IR (KBr): υ 3072 ( C H, Ar-H), 1674 (C O, pyrazolone), 1616 (C N),
1548 (C C). 1H NMR (400 MHz, CDCl3): δ 2.44 (s, 3H, CH3 of pyrazolone), 3.18 (s, 6H,
N,N-dimethyl), 6.76 (d, 2H, J = 9.2Hz, ArH), 7.22 (s, 1H, ArH), 7.35–7.38 (m, 3H, 2H-ArH
and 1H, Ar-CH ), 7.92 (d, 2H, 1H-ArH, 1H-thiazole), 8.57 (d, 2H, J = 8.4Hz, ArH).13C
NMR (CDCl3 δ ppm): 13.5, 40.0, 107.5, 111.4, 117.2, 121.6, 127.7, 128.5, 132.9, 133.4,
137.9, 149.2, 149.6, 154.3, 154.5, 155.5 and 162.1. EI-MS 423 [M+H]+. Anal. calcd. for
C22H19ClN4OS: C, 62.48; H, 4.53; N, 13.25; Found: C, 62.38; H, 5.15; N, 13.20.
4-(4-Methylbenzylidene)-1-(4-(4-chlorophenyl)thiazol-2-yl)-
3-methyl-1H-pyrazol-5(4H)-one (5c)
Yellow solid; IR (KBr): υ 3051 ( C H, Ar-H), 1681 (C O, pyrazolone), 1606
1
(C N), 1573 (C C). H NMR (400 MHz, DMSO-d6): δ 2.30 (s, 3H, Ar-CH3), 2.46 (s,
3H, CH3 of pyrazolone), 7.22–7.26 (m, 4H, ArH), 7.49–7.51 (m, 5H, 4H-ArH and 1H,
Ar-CH ), 7.98 (s, 1H, thiazole), Anal. calcd. for C21H16ClN3OS: C, 64.03; H, 4.09; N,
10.67; Found: C, 64.10; H, 4.12; N, 10.62.

ONE-POT SYNTHESIS OF THIAZOLYL-PYRAZOLONES
493
4-(4-Methoxybenzylidene)-1-(4-(4-chlorophenyl)thiazol-2-yl)-
3-methyl-1H-pyrazol-5(4H)-one (5d)
Yellow solid; IR (KBr): υ 3082 ( C H, Ar-H), 1681 (C O, pyrazolone), 1606
1
(C N), 1573 (C C). H NMR (400 MHz, CDCl3): δ 2.08 (s, 3H, CH3 of pyrazolone),
3.81 (s, 3H, CH3 of methoxy), 6.85–6.92 (m, 3H, ArH), 7.16–7.30 (m, 4H, 3H-ArH and
1H, Ar-CH ), 7.42–7.44 (m, 3H, 2H-ArH, 1H-thiazole). 13C NMR (CDCl3 δ ppm): 13.5,
54.0, 107.6, 111.9, 117.3, 121.6, 128.1, 128.6, 132.9, 133.4, 138.7, 149.2, 149.9, 154.3,
154.4, 155.6 and 163.4. EI-MS 410 [M+H]+. Anal. calcd. for C21H16ClN3O2S: C, 61.53;
H, 3.93; N, 10.25; Found: C, 61.50; H, 3.97; N, 10.21.
4-(4-Chlorobenzylidene)-1-(4-(4-chlorophenyl)thiazol-2-yl)-
3-methyl-1H-pyrazol-5(4H)-one (5e)
Yellow solid; IR (KBr): υ 3064 ( C H, Ar-H), 1681 (C O, pyrazolone), 1595
(C N), 1571 (C C). 1H NMR (400 MHz, DMSO-d6): δ 2.51 (s, 3H, CH3 of pyrazolone),
7.24–7.30 (m, 4H, ArH), 7.36–7.49 (m, 3H, 2H-ArH, 1H, Ar-CH ), 7.63 (d, 2H, J =
6.6Hz, ArH), 8.01 (s, 1H, thiazole). 13C NMR (CDCl3 +DMSO-d6 δ ppm): 13.6, 106.4,
112.4, 116.6, 122.6, 124.6, 127.7, 129.0, 133.3, 138.6, 148.8, 151.8, 152.9, 154.3, 155.2
and 162.0. EI-MS 436 [M+Na]+. Anal. calcd. for C20H13Cl2N3OS: C, 57.98; H, 3.16; N,
10.14; Found: C, 57.92; H, 3.19; N, 10.18.
4-(2-Hydroxybenzylidene)-1-(4-(4-chlorophenyl)thiazol-2-yl)-3-methyl-
1H-pyrazol-5(4H)-one (5f)
Yellow solid; IR (KBr): υ 3109 (-OH), 3068 ( C H, Ar-H), 1693 (C O, pyra-
zolone), 1622 (C N), 1581 (C C). 1H NMR (400 MHz, DMSO-d6): δ 1.90 (s, 3H, CH3
of pyrazolone), 6.90 (d, 2H, J = 9.2Hz, ArH), 7.22 (s, 1H, ArH), 7.39 (s, 1H, ArH), 7.47
(d, 2H, J = 9.2Hz, ArH), 7.62 (s, 1H, Ar-CH ), 7.87 (d, 2H, J = 9.2Hz, ArH), 8.32 (s, 1H,
thiazole), 10.11 (s, 1H, OH, D2O exchangeable), EI-MS 396 [M+H]+. Anal. calcd. for
C20H14ClN3O2S: C, 60.68; H, 3.56; N, 10.61; Found: C, 60.70; H, 3.59; N, 10.65.
4-(5-Bromo-2-hydroxybenzylidene)-1-(4-(4-chlorophenyl)thiazol-
2-yl)-3-methyl-1H-pyrazol-5(4H)-one (5g)
Yellow solid; IR (KBr): υ 3111 ( OH), 3051 ( C H, Ar-H), 1691 (C O, pyra-
zolone), 1616 (C N), 1589 (C C). 1H NMR (400 MHz, DMSO-d6): δ 1.90 (s, 3H, CH3
of pyrazolone), 6.87 (s, 1H, ArH), 7.34–7.47 (m, 4H, ArH), 7.74 (s, 1H, Ar-CH ), 7.87
(d, 2H, J = 7Hz, ArH), 8.25 (s, 1H, thiazole), 10.40 (s, 1H, -OH, D2O exchangeble), Anal.
calcd. For C20H13BrClN3O2S: C, 50.60; H, 2.76; N, 8.85; Found: C, 50.64; H, 2.79; N,
8.81.
4-(3,5-Bibromo-2-hydroxybenzylidene)-1-(4-(4-chlorophenyl)thiazol-
2-yl)-3-methyl-1H-pyrazol-5(4H)-one (5h)
Yellow solid; IR (KBr): υ 3107 ( OH), 3068 ( C H, Ar-H), 1691 (C O, pyra-
1
zolone), 1610 (C N), 1585 (C C). H NMR (400 MHz, CDCl3): δ 2.13 (s, 3H, CH3

494
C. S. R. VENKATA AND V. RAJESWAR RAO
of pyrazolone), 6.79 (s, 1H, ArH), 7.05 (s, 1H, ArH), 7.41 (d, 2H, J = 9.2Hz, ArH),
7.63–7.65 (m, 3H, 2H-ArH and 1H, Ar-CH ), 7.71 (s, 1H, thiazole), 10.85 (s, 1H, -OH,
D2O exchangeable). 13C NMR (CDCl3 +DMSO-d6 δ ppm): 17.5, 106.2, 110.8, 117.2,
121.6, 123.0, 127.6, 127.9, 128.5, 132.8, 133.3, 137.0, 149.2, 149.6, 154.3, 155.6, 156.4,
and 161.1. EI-MS 552 [M+2]+. Anal. calcd. for C20H12Br2ClN3O2S: C, 43.39; H, 2.18;
N, 7.59; Found: C, 43.34; H, 2.15; N, 7.56.
4-(5-Chloro-2-hydroxybenzylidene)-1-(4-(4-chlorophenyl)thiazol-2-yl)-
3-methyl-1H-pyrazol-5(4H)-one (5i)
Yellow solid; IR (KBr): υ 3109 ( OH), 3057 ( C H, Ar-H), 1695 (C O, pyra-
zolone), 1618 (C N), 1587 (C C). 1H NMR (400 MHz, CDCl3): δ 1.90 (s, 3H, CH3 of
pyrazolone), 6.93 (d, 1H, J = 9.2Hz, ArH), 7.24–7.27 (m, 1H, ArH), 7.39 (s, 1H, ArH),
7.47 (d, 2H, J = 9.2Hz ArH), 7.61 (s, 1H, Ar-CH ), 7.87 (d, 2H, J = 9.2Hz ArH), 8.26
(s, 1H, thiazole), Anal. calcd. for: C20H13Cl2N3O2S: C, 55.82; H, 3.05; N, 9.77; Found: C,
55.82; H, 3.10; N, 9.75.
4-(4-(Dimethylamino)benzylidene)-1-(4-(4-bromophenyl)thiazol-2-yl)-
3-methyl-1H-pyrazol-5(4H)-one (5j)
Red solid; IR (KBr): υ 3057 ( C H, Ar-H), 1687 (C O, pyrazolone), 1624 (C N),
1577 (C C). 1H NMR (400 MHz, DMSO-d6): δ 2.37 (s, 3H, CH3 of pyrazolone), 3.17 (s,
6H, N,N-dimethyl), 6.91 (d, 2H, J = 9.2Hz, ArH), 7.51 (d, 2H, J = 7Hz, ArH), 7.73 (s, 1H,
Ar-CH ), 7.85 (s, 1H, ArH), 7.98–8.00 (d, 2H, 1H-ArH, 1H-thiazole), 8.63 (d, 2H, J =
9.2Hz, ArH). Anal. calcd. for: C22H19BrN4OS: C, 56.54; H, 4.10; N, 11.99; Found: C,
56.51; H, 4.14; N, 11.95.
4-(5-Bromo-2-hydroxybenzylidene)-1-(4-(4-bromophenyl)thiazol-2-yl)-
3-methyl-1H-pyrazol-5(4H)-one (5k)
Yellow solid; IR (KBr): υ 3109 ( OH), 3057 ( C H, Ar-H), 1691 (C O, pyra-
zolone), 1616 (C N), 1587 (C C). 1H NMR (400 MHz, DMSO-d6): δ 1.90 (s, 3H, CH3 of
pyrazolone), 6.87 (d, 1H, J = 9.2Hz ArH), 7.34–7.48 (m, 4H, ArH), 7.74 (s, 1H, Ar-CH ),
7.87 (d, 2H, J = 9.2Hz, ArH), 8.25 (s, 1H, thiazole), 10.41 (s, 1H, -OH, D2O exchangeable),
Anal. calcd. for: C20H13Br2N3O2S: C, 46.27; H, 2.52; N, 8.09; Found: C, 46.25; H, 2.55;
N, 8.10.
4-(3,5-Dibromo-2-hydroxybenzylidene)-1-(4-(4-bromophenyl)thiazol-
2-yl)-3-methyl-1H-pyrazol-5(4H)-one (5l)
Yellow solid; IR (KBr): υ 3107 ( OH), 3032 ( C H, Ar-H), 1689 (C O, pyra-
zolone), 1608 (C N), 1568 (C C). 1H NMR (400 MHz, DMSO-d6): δ 1.90 (s, 3H, CH3
of pyrazolone), 7.47 (s, 1H, Ar-CH ), 7.62 (d, 2H, J = 9.2Hz, ArH), 7.76–7.82 (m, 4H,
ArH), 8.26 (s, 1H, thiazole), 10.87 (s, 1H, OH, D2O exchangeable), Anal. calcd. for:
C20H12Br3N3O2S: C, 40.16; H, 2.02; N, 7.03; Found: C, 40.12; H, 2.55; N, 7.10.

ONE-POT SYNTHESIS OF THIAZOLYL-PYRAZOLONES
495
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