Synthesis of coumarin-substituted thiazolyl-pyrazolone derivatives via one-pot reaction

Article abstract of DOI:10.1080/17415993.2010.513439

An efficient multi-component reaction for the preparation of 4-arylidene-3-methyl-1-4-[2-oxo-2H-chromen-3-yl)thiazol-2-yl]-1H-pyrazol-5(4H) -ones 5 has been described. The synthesis process involves the simultaneous formation of two heterocycles such as thiazole and pyrazolone along with the condensation of an active methylene group by aldehydes via the Knoevenagel reaction.

Full text of DOI:10.1080/17415993.2010.513439

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Synthesis of coumarin-substituted
thiazolyl-pyrazolone derivatives via
one-pot reaction
Venkata S.R. Chunduru a & Vedula Rajeswar Rao a
a Department of Chemistry, National Institute of Technology,
Warangal, 506 004, Andhra Pradesh, India
Version of record first published: 28 Sep 2010
To cite this article: Venkata S.R. Chunduru & Vedula Rajeswar Rao (2010): Synthesis of coumarin-
substituted thiazolyl-pyrazolone derivatives via one-pot reaction, Journal of Sulfur Chemistry, 31:6,
545-550
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Journal of Sulfur Chemistry
Vol. 31, No. 6, December 2010, 545–550
Synthesis of coumarin-substituted thiazolyl-pyrazolone
derivatives via one-pot reaction
Venkata S.R. Chunduru and Vedula Rajeswar Rao*
Department of Chemistry, National Institute of Technology, Warangal-506 004, Andhra Pradesh, India
(Received 17 June 2010; final version received 1 August 2010)
An efficient multi-component reaction for the preparation of 4-arylidene-3-methyl-1-4-[2-oxo-2H-
chromen-3-yl)thiazol-2-yl]-1H-pyrazol-5(4H)-ones 5 has been described. The synthesis process involves
thesimultaneousformationoftwoheterocyclessuchasthiazoleandpyrazolonealongwiththecondensation
of an active methylene group by aldehydes via the Knoevenagel reaction.
Keywords: 3-(2-bromoacetyl)coumarin; thiazole; pyrazolone; thiosemicarbazide; multi-component
reaction
1. Introduction
Coumarin and its derivatives are biologically active compounds (1), widely occurring in nature.
The synthesis of coumarin derivatives has attracted a considerable attention of organic and medic-
inal chemists because they have shown a remarkably broad spectrum of pharmacological and
physiological activities. Coumarin derivatives are used as anticoagulant (2, 3), antibacterial (4),
antiviral (5), antitumor (6, 7), bactericidal (8), fungicidal (9) and anti-inflammatory agents (10).
Also, in recent times, these are references to derivatives with an anti-HIV activity (11, 12).
On the other hand, the nitrogen and sulfur heterocyclic systems are very interesting because of
their physicochemical properties with relevance to the design of new drugs and new materials. In
that respect, compounds containing the thiazole ring system are known to possess pharmacological
properties such as analgesic, antibacterial, anticonvulsant, antiparasitic, anti-inflammatory and
herbicidal activities (13–16). Some derivatives of thiazole are potent anti-HIV agents (17). It is
also known that various therapeutic activities have been reported for pyrazoles (18, 19).
In view of the various physiological activities of coumarins, thiazoles and pyrazoles, our current
studies are focussed on the development of new routes for the synthesis of thiazoles incorporating
pyrazole and coumarin moieties. So we have developed a one-pot multi-component reaction
(MCR) for the synthesis of a target molecule, because it, consisting of two or more synthetic steps,
*Corresponding author. Email: vrajesw@yahoo.com
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2010 Taylor & Francis
DOI: 10.1080/17415993.2010.513439
http://www.informaworld.com

546 V.S.R. Chunduru and V.R. Rao
which are carried out without the isolation of any intermediate, led to reduce time and save money,
energy and raw materials. Multi-component processes are at a premium for the achievement of
high levels of diversity and brevity, as they allow three or more simple and flexible building blocks
to be combined in practical, one-pot operations (20, 21).
2. Results and discussion
Generally, thiazoles are synthesized by Hantzsch synthesis, where α-halo ketones were condensed
with thiourea (22, 23). Moriarty and Prakash have recently reported thiazole synthesis by using α-
tosyloxy ketones instead of α-halo carbonyl compounds (24). These methods give excellent yields
for simple thiazoles. However, for some substituted examples, low yields have been reported as
a result of dehalogenation of the α-haloketone during the reaction.
In continuation of our earlier work on the synthesis of heterocyclic systems derived from
coumarins (25, 26), we report herein a MCR that involves Hantzsch-thiazole synthesis and
the formation of pyrazolone skeleton simultaneously. In this method, equimolar amounts of
3-(2-bromoacetyl)coumarin, thiosemicarbazide and ethyl acetoacetate were taken in acetic
acid, heated at 50–55◦C which gave 3-methyl-1-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl]-1H-
pyrazol-5(4H)-one having an active methylene group. Without isolating this intermediate,
we have added sodium acetate and aryl aldehyde to the reaction mass. This intermediate
undergoes aldol condensation followed by an intramolecular dehydration to give the target
product 5.
The IR spectrum of compound 5a shows prominent peaks at 1675 cm−1 for –C O of pyra-
=
1
zolone and 1716 cm−1 for coumarin lactone. H NMR of compound 5a shows characteristic
singlets for –CH3 of pyrazolone at δ 2.47 and N,N-dimethyl at δ 3.19 and the C-4 proton of
thiazole at δ 8.29. The C-4 proton of coumarin shows the singlet at δ 8.89. The above spectral
1
data confirm the structure of compound 5a. In the same way, the H NMR of compound 5g
shows characteristic singlets for –CH3 of pyrazolone at δ 2.50, –OCH3 at δ 3.94, the C-4 proton
of thiazole at δ 8.31 and the C-4 proton of coumarin at δ 8.86, also confirming the structure
of 5g.
R
CHO
S
R
O
O
O
AcOH/AcONa
O
O
+
H2N
Br
+
+
OEt
NH2
O
O
N
CH3
R1
H
N
N
N
R1
R2
4
H
1
3
2
S
O
5
R2
R1
H
R2
R
H
R1
R2
R
g
H
OMe
5a
b
c
d
e
f
H
NMe2
5,6-benzo analog of 5g
h
i
j
k
l
5,6-benzo analog of 5a
H
Cl
OMe
OMe
Cl
H
Cl
Cl Cl
Br
Br Br
NMe2
NMe 2
NMe2
NMe2
Cl Cl
H
H
H
H
H
Me
Scheme1. Synthesisof4-arylidene-3-methyl-1-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl]-1H-
pyrazol- 5(4H)-ones.

Journal of Sulfur Chemistry 547
3. Conclusion
In conclusion, a multi-component one-pot synthesis of 4-arylidene-3-methyl-1-[4-(2-oxo-2H-
chromen-3-yl)thiazol-2-yl]-1H-pyrazol-5(4H)-ones 5 has been achieved under neat reaction
conditions using commercially available starting materials. This method provides various advan-
tages, such as good yields, neat reaction conditions and easy workup. These new derivatives may
be beneficially utilized in the drug research. The biological activity of these compounds is in
progress.
4. Experimental
4.1. General
All the reagents and solvents were pure, purchased from commercial sources and were used with-
out further purification unless otherwise stated. 3-(2-Bromoacetyl)coumarins (27) were prepared
by the literature procedure. Melting points were determined in open capillaries with a “Cin-
tex” melting point apparatus Mumbai, India, and were uncorrected. CHNS analysis was done by
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 the standard. Electron ionization mass spectra (EI-MS) were determined on
Perkin Elmer (SCIEX API-2000, ESI) at 12.5 eV.
4.2. General procedure for the synthesis of 4-arylidene-3-methyl-1-[4-(2-oxo-2H-chromen-
3-yl)thiazol-2-yl]-1H-pyrazol-5(4H)-ones (5a–l)
3-(2-Bromoacetyl)coumarin (1 mmol), thiosemicarbazide (1 mmol) and ethyl acetoacetate
(1 mmol) were taken in 10 ml of acetic acid, heated at 50–55◦C for about 2 h. The reaction
mixture was cooled to room temperature, 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.
4.3. 4-(4-(Dimethylamino)benzylidene)-3-methyl-1-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-
yl]-1H-pyrazol-5(4H)-one (5a)
Yield 82%, m.p.>300◦C, color: red; IR (KBr, υ): 1716, 1675, 1566, 1516. 1H NMR (400 MHz,
CDCl3): δ 2.47 (s, 3H, CH3 of pyrazolone), 3.19 (s, 6H, N,N-dimethyl), 6.77 (d, 2H, J = 9.2 Hz,
−
=
ArH), 7.28–7.40 (m, 3H, ArH), 7.50–7.66 (m, 2H, 1H-ArH and 1H, Ar CH ), 8.29 (s, 1H,
thiazole), 8.57 (d, 2H, J = 9.2 Hz, ArH), 8.89 (s, 1H, C-4 of coumarin). EI-MS 457 [M+ H]+.
Anal. calcd. for C25H20N4O3S: C, 65.77; H, 4.42; N, 12.27. Found: C, 65.68; H, 4.31; N, 12.32%.
4.4. 4-(4-(Dimethylamino)benzylidene)-3-methyl-1-[4-(3-oxo-3H-benzo[f]chromen-2-
yl)thiazol-2-yl]-1H-pyrazol-5(4H)-one (5b)
Yield 75%, m.p.>300◦C, color: red; IR (KBr, υ): 1728, 1673, 1566, 1517. 1H NMR (400 MHz,
CDCl3): 2.50 (s, 3H, CH3 of pyrazolone), 3.19 (s, 6H, N,N-dimethyl), 6.78 (d, 2H, J = 9.2 Hz,
−
=
ArH), 7.42–7.99 (m, 6H, 5H-ArH and 1H, Ar CH ), 8.36 (s, 1H, thiazole), 8.62–8.64 (m, 3H,

548 V.S.R. Chunduru and V.R. Rao
ArH), 9.62 (s, 1H, C-4 of coumarin). Anal. calcd. for C29H22N4O3S: C, 68.76; H, 4.38; N, 11.06.
Found: C, 68.69; H, 4.43; N, 10.96%.
4.5. 4-(4-(Dimethylamino)benzylidene)-1-[4-(6-chloro-2-oxo-2H-chromen-3-yl)thiazol-2-
yl]-3-methyl-1H-pyrazol-5(4H)-one (5c)
Yield 82%, m.p.>300◦C, color: red; IR (KBr, υ): 1727, 1672, 1568, 1516. 1H NMR (400 MHz,
CDCl3): δ 2.47 (s, 3H, CH3 of pyrazolone), 3.19 (s, 6H, N,N-dimethyl), 6.78 (d, 2H, J = 9.2 Hz,
−
=
ArH), 7.21–7.34 (m, 1H, ArH), 7.40–7.49 (m, 2H, ArH), 7.60 (s, 1H, Ar CH ), 8.30 (s, 1H,
thiazole), 8.58 (d, 2H, J = 9.2 Hz, ArH), 8.81 (s, 1H, C-4 of coumarin ArH). Anal. calcd. for
C25H19·ClN4O3S: C, 61.16; H, 3.90; N, 11.41. Found: C, 61.01; H, 3.84; N, 11.49%.
4.6. 4-(4-(Dimethylamino)benzylidene)-1-[4-(6,8-dichloro-2-oxo-2H-chromen-3-yl)thiazol-
2-yl]-3-methyl-1H-pyrazol-5(4H)-one (5d)
Yield 80%, m.p.>300◦C, color: red; IR (KBr, υ): 1728, 1672, 1568, 1517. 1H NMR (400 MHz,
CDCl3): δ 2.47 (s, 3H, CH3 of pyrazolone), 3.19 (s, 6H, N,N-dimethyl), 6.78 (d, 2H, J = 9.2 Hz,
−
=
ArH), 7.21–7.35 (m, 1H, ArH), 7.417.56 (m, 1H, ArH), 7.60 (s, 1H, Ar CH ), 8.30 (s, 1H,
thiazole), 8.60 (d, 2H, J = 9.2 Hz, ArH), 8.81 (s, 1H, C-4 of coumarin ArH). Anal. calcd. for
C25H18Cl2N4O3S: C, 57.15; H, 3.45; N, 10.66. Found: C, 57.26; H, 3.41; N, 10.59%.
4.7. 4-(4-(Dimethylamino)benzylidene)-1-[4-(6-bromo-2-oxo-2H-chromen-3-yl)thiazol-2-
yl]-3-methyl-1H-pyrazol-5(4H)-one (5e)
Yield 84%, m.p.>300◦C, color: red; IR (KBr, υ): 1737, 1674, 1568, 1519. 1H NMR (400 MHz,
CDCl3): δ 2.48 (s, 3H, CH3 of pyrazolone), 3.23 (s, 6H, N,N-dimethyl), 6.77 (d, 2H, J = 9.2 Hz,
−
=
ArH), 7.329–7.70 (m, 4H, 3H-ArH and 1H, Ar CH ), 8.34 (s, 1H, thiazole), 8.56 (d, 2H,
J = 9.2 Hz, ArH), 8.85 (s, 1H, C-4 of coumarin). Anal. calcd. for C25H19BrN4 O3S: C, 56.08; H,
3.58; N, 10.46. Found: C, 56.20; H, 3.62; N, 10.51%.
4.8. 4-(4-(Dimethylamino)benzylidene)-1-[4-(6,8-dibromo-2-oxo-2H-chromen-3-yl)thiazol-
2-yl]-3-methyl-1H-pyrazol-5(4H)-one (5f)
Yield 85%, m.p.>300◦C, color: red; IR (KBr, υ): 1737, 1674, 1569, 1516. 1H NMR (400 MHz,
DMSO-d6): δ 2.37 (s, 3H, CH3 of pyrazolone), 3.16 (s, 6H, N,N-dimethyl), 6.90 (d, 2H, J =
−
=
9.2 Hz, ArH), 7.31–7.40 (m, 1H, ArH), 7.72–7.78 (m, 1H, ArH), 7.95 (s, 1H, Ar CH ), 8.31
(s, 1H, thiazole), 8.65 (d, 2H, J = 9.2 Hz, ArH), 8.71 (s, 1H, C-4 of coumarin). Anal. calcd. for
C25H18 Br2N4O3S: C, 48.88; H, 2.95; N, 9.12. Found: C, 48.95; H, 2.91; N, 9.17%.
4.9. 4-(4-Methoxybenzylidene)-3-methyl-1-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl]-1H-
pyrazol-5(4H)-one (5g)
Yield 80%, m.p.>300◦C, color: yellow; IR (KBr, υ): 1708, 1678, 1558, 1510. 1H NMR (400 MHz,
CDCl3): δ 2.50 (s, 3H, CH3 of pyrazolone), 3.94 (s, 3H, CH3 of methoxy), 7.06 (d, 2H, J = 9.2 Hz,
−
=
ArH), 7.29–7.38 (m, 3H, ArH), 7.51–7.67 (m, 2H, 1H-ArH and 1H, Ar CH ), 8.31 (s, 1H,
thiazole), 8.62 (d, 2H, J = 9.2 Hz, ArH), 8.86 (s, 1H, C-4 of coumarin). EI-MS 444 [M+ H]+.
Anal. calcd. for C24H17 N3O4S: C, 65.00; H, 3.86; N, 9.48. Found: C, 64.96; H, 3.91; N, 9.59%.

Journal of Sulfur Chemistry 549
4.10. 4-(4-Methoxybenzylidene)-3-methyl-1-[4-(3-oxo-3H-benzo[f]chromen-2-yl)thiazol-2-
yl]-1H-pyrazol-5(4H)-one (5h)
Yield 76%, m.p.>300◦C, color: yellow; IR (KBr, υ): 1715, 1680, 1554, 1511. 1H NMR (400 MHz,
CDCl3): δ 2.53 (s, 3H, CH3 of pyrazolone), 3.94 (s, 3H, CH3 of methoxy), 6.93 (d, 2H, J = 9.2 Hz,
−
=
ArH), 7.50–7.99 (m, 7H, 6H-ArH and 1H, Ar CH ), 8.38 (s, 1H, thiazole), 8.62–8.65 (m, 2H,
ArH), 9.30 (s, 1H, C-4 of coumarin). Anal. calcd. for C28H19 N3O4S: C, 68.14; H, 3.88; N, 8.51.
Found: C, 68.25; H, 3.80; N, 8.57%.
4.11. 4-(4-Methoxybenzylidene)-1-[4-(6-chloro-2-oxo-2H-chromen-3-yl)thiazol-2-yl]-3-
methyl-1H-pyrazol-5(4H)-one (5i)
Yield 79%, m.p.>300◦C, color: yellow; IR (KBr, υ): 1714, 1685, 1555, 1509. 1H NMR (400 MHz,
DMSO-d6): δ 2.50 (s, 3H, CH3 of pyrazolone), 3.94 (s, 3H, CH3 of methoxy), 7.06 (d, 2H,
−
=
J = 9.2 Hz, ArH), 7.30–7.55 (m, 3H, ArH), 7.62 (s, 1H, Ar CH ), 8.42 (s, 1H, thiazole), 8.61
(d, 2H, J = 9.2 Hz, ArH), 8.77 (s, 1H, C-4 of coumarin ArH). Anal. calcd. for C24H16 ClN3O4S:
C, 60.31; H, 3.37; N, 8.79. Found: C, 60.27; H, 3.42; N, 8.71%.
4.12. 4-(4-Methoxybenzylidene)-1-[4-(6,8-dichloro-2-oxo-2H-chromen-3-yl)thiazol-2-yl]-3-
methyl-1H-pyrazol-5(4H)-one (5j)
Yield 82%, m.p.>300◦C, color: yellow; IR (KBr, υ): 1714, 1685, 1555, 1509. 1H NMR (400 MHz,
CDCl3+DMSO-d6): δ 2.50 (s, 3H, CH3 of pyrazolone), 3.95 (s, 3H, CH3 of methoxy), 7.08 (d,
−
=
2H, J = 9.2 Hz, ArH), 7.34–7.66 (m, 3H, 2H-ArH and 1H, Ar CH ), 8.32 (s, 1H, thiazole),
8.63 (d, 2H, J = 9.2 Hz, ArH), 8.77 (s, 1H, C-4 of coumarin). Anal. calcd. for C24H15Cl2 N3O4S:
C, 56.26; H, 2.95; N, 8.20. Found: C, 56.35; H, 2.89; N, 8.27%.
4.13. 4-(4-Chlorobenzylidene)-3-methyl-1-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl]-1H-
pyrazol-5(4H)-one (5k)
Yield 80%, m.p.>300◦C, color: yellow; IR (KBr, υ): 1715, 1685, 1555, 1508. 1H NMR
(400 MHz, CDCl3): δ 2.40 (s, 3H, CH3 of pyrazolone), 7.31–7.37 (m, 4H, ArH), 7.51–7.62
−
=
(m, 4H, ArH), 7.87 (s, 1H, Ar CH ), 7.91 (s, 1H, thiazole), 8.51 (s, 1H, C-4 of coumarin).
Anal. calcd. for C23H14ClN3O3S: C, 61.68; H, 3.15; N, 9.38. Found: C, 61.72; H, 3.11;
N, 9.31%.
4.14. 4-(4-Methylbenzylidene)-3-methyl-1-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl]-1H-
pyrazol-5(4H)-one (5l)
Yield 79%, m.p.>300◦C, color: yellow; IR (KBr, υ): 1728, 1686, 1553, 1509. 1H NMR (400 MHz,
CDCl3): δ 2.33 (s, 3H, Ar-CH3), 2.44 (s, 3H, CH3 of pyrazolone), 7.25 (d, 2H, J = 7 Hz, ArH),
−
=
7.38–7.66 (m, 5H, ArH), 7.77 (s, 1H, Ar CH ), 7.86 (d, 1H, J = 9.2 Hz, ArH), 8.03 (s, 1H,
thiazole), 8.54 (s, 1H, C-4 of coumarin). Anal. calcd. for C24H17N3O3S: C, 67.43; H, 4.01; N,
9.83. Found: C, 67.39; H, 3.97; N, 9.90%.
Acknowledgement
The authors are thankful to the Director, National Institute of Technology, Warangal, for providing financial support and
facilities.

550 V.S.R. Chunduru and V.R. Rao
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