New, convenient, one-pot method for the synthesis of thiazolyl-pyrazolones from dehydroacetic acid derivative via a multicomponent approach

Article abstract of DOI:10.1080/00397911.2011.558969

A convenient one-pot method for the synthesis of thiazolyl-pyrazolones was described in excellent yields. Reaction of 3-(2-bromoacetyl)-4-hydroxy-6-methyl- 2H-pyran-2-one with thiosemicarbazide and ethyl 2-(2-arylhydrazono)-3- oxobutanoates in anhydrous ethanol under reflux conditions afforded the corresponding 4-(2-arylhydrazono)-1-(4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl) thiazol-2-yl)-3-methyl-1H-pyrazol-5(4H)-one in good yields. The structures of newly synthesized compounds were established on the basis of elemental analysis, infrared, ¹H NMR, and mass spectroscopic studies.

Full text of DOI:10.1080/00397911.2011.558969

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New, Convenient, One-Pot Method for
the Synthesis of Thiazolyl-pyrazolones
from Dehydroacetic Acid Derivative via a
Multicomponent Approach
Santhosh Penta a & Rajeswar Rao Vedula a
a Department of Chemistry, National Institute of Technology,
Warangal, India
Accepted author version posted online: 08 May 2012. Version of
record first published: 02 Aug 2012
To cite this article: Santhosh Penta & Rajeswar Rao Vedula (2012): New, Convenient, One-Pot Method
for the Synthesis of Thiazolyl-pyrazolones from Dehydroacetic Acid Derivative via a Multicomponent
Approach, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 42:23, 3395-3402
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Synthetic Communications1, 42: 3395–3402, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.558969
NEW, CONVENIENT, ONE-POT METHOD FOR THE
SYNTHESIS OF THIAZOLYL-PYRAZOLONES FROM
DEHYDROACETIC ACID DERIVATIVE VIA A
MULTICOMPONENT APPROACH
Santhosh Penta and Rajeswar Rao Vedula
Department of Chemistry, National Institute of Technology, Warangal, India
GRAPHICAL ABSTRACT
Abstract A convenient one-pot method for the synthesis of thiazolyl-pyrazolones was
described in excellent yields. Reaction of 3-(2-bromoacetyl)-4-hydroxy-6-methyl-2H-
pyran-2-one with thiosemicarbazide and ethyl 2-(2-arylhydrazono)-3-oxobutanoates in
anhydrous ethanol under reflux conditions afforded the corresponding 4-(2-arylhydra-
zono)-1-(4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)thiazol-2-yl)-3-methyl-1H-pyrazol-
5(4H)-one in good yields. The structures of newly synthesized compounds were established
on the basis of elemental analysis, infrared, 1H NMR, and mass spectroscopic studies.
Keywords Aromatic primary amine; 3-(2-bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-
one; multicomponent reactions; one-pot synthesis; thiazolyl-pyrazolone; thiosemicarbazide
INTRODUCTION
Heterocycles are widely used in the development of modern pharmaceuticals.
This is one of the reasons why continuous efforts are made toward the design of
amenable synthetic approaches for the synthesis of new heterocyclic systems. The het-
erocyclic compounds thiazoles play a prominent role in nature as they are found in
numerous biologically active compounds. Thiazole derivatives are exhibit significant
biological activities such as antitubercular,[1] antifungal,[2] analgesic,[3] and anticancer
activity.[4] Pyrazoles, as key substructures in a large variety of compounds with
Received October 11, 2010.
Address correspondence to Rajeswar Rao Vedula, Department of Chemistry, National Institute of
Technology, Warangal 506001, India. E-mail: vrajesw@yahoo.com
3395

3396
S. PENTA AND R. R. VEDULA
important medicinal and pesticidal properties, have attracted much attention.[5–7]
Pyrazoles can be effectively utilized as antibacterial, antifungal, antiviral, antiparasi-
tic, antitubercular, antidepressant, and insecticidal agents, and considerable attention
has been focused on this class.[8–12] In addition, pyrazoles have played a crucial part in
the development of heterocyclic chemistry and are also used extensively in organic
synthesis.[13] 3-Acetyl-4-hydroxy-6-methyl-2H-pyran-2-one (dehydroacetic acid,
DHA) is a versatile starting material, and its derivatives find wider application in
[14–16]
the synthesis of heterocyclic compounds.
Multicomponent reactions (MCRs) are processes ‘‘in which more than two
reactants directly get converted into their products by one-pot reaction.’’[17] MCRs
play an important role in modern organic chemistry, because they generally exhibit
great atom economy and selectivity as well as produce fewer by-products compared
to classical multistep synthesis.[18] Further, in many cases, MCRs are easy to perform,
inexpensive, and quick; consume less energy; and involve simple experimental
procedures.[19] The first MCR was described in 1850 by Strecker,[20] and thereafter
many such reactions have been reported in the literature.[21]
In view of the various biological activities of thiazoles and pyrazoles, our
current studies are focused on the development of new routes for the synthesis of
thiazolyl-pyrazolones with 3-(2-bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one.
We have developed a one-pot, multicomponent reaction for the synthesis of
substituted aryl hydrazono thiazolyl-pyrazolone derivatives. Hydrazono thiazolyl-
pyrazolone derivatives were synthesized by Kalluraya et al.[22] in a stepwise manner.
In this method, diazotization of ethyl acetoacetate with various aryldiazonium salts in
the presence of sodium acetate in ethanol medium afforded the corresponding
ethyl-2-arylhydrazono-3-oxobutyrates, which on reaction with thiosemicarbazide
gave the respective thioamides. Reaction of these thioamides with 3-(2-bromoacetyl)
coumarins in a dimethylformamide (DMF)–ethanol mixture gave the title products.
However, this method has some limitations, such as harsh reaction conditions, and
suffers from multistep synthesis, longer reaction times, and poor yields. Therefore
there is still lack of a general, efficient, and one-pot method for the synthesis of
substituted aryl hydrazono thiazolyl-pyrazolone.
RESULTS AND DISCUSSION
In continuation of our earlier work on the synthesis of different heterocyclic sys-
tems,[23–25] we report herein a facile, one-pot method for the synthesis of substituted
phenyl hydrazono thiazolyl-pyrazolones from a three-component reaction. Reaction
of an equimolar mixture of 3-(2-bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one
(1), thiosemicarbazide (2), and ethyl 2-(2-phenylhydrazono)-3-oxobutanoate (3)
under reflux in anhydrous ethanol gave the final products 4-(2-arylhydrazono)-1-
(4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)thiazol-2-yl)-3-methyl-1H-pyrazol-5(4-
H)-one (4) (Scheme 1).
In this reaction, a plausible mechanism for the formation of 4 can be proposed
(Scheme 2). The bromine atom of 3-(2-bromoacetyl)-4-hydroxy-6-methyl-2H-
pyran-2-one is replaced by a sulfur atom of thiosemicarbazide to yield an open-chain
a-thio ketone, which under trans-protonation proceeds to give 4-hydroxy thiazoline
derivative (A). This subsequently undergoes dehydration to give 2-hydrazino thiazole

THIAZOLYL-PYRAZOLONES
3397
Scheme 1. 4-(2-Arylhydrazono)-1-(4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)thiazol-2-yl)-3-methyl-1-
H-pyrazol-5(4H)-one.
derivative (in situ). This subsequently undergoes a condensation reaction with
ethyl-2-(2-aryl hydrazono)-3-oxo butanoate to give final product 4.
The structures of newly prepared compounds have been established on the basis
of elemental analysis and spectral data. The IR spectrum of compouꢀn1d 4b showed
prominent peaks at 1676 cmꢀ1 for –C O of pyrazolone, at 1694 cm for lactone
=
1
carbonyl, at 3374 cmꢀ1 for –NH, and 3407 cmꢀ1 for -OH, whereas the H NMR of
Scheme 2. Plausible mechanism.

3398
S. PENTA AND R. R. VEDULA
compound 4b showed characteristic singlets for -CH3 groups at d 2.26, 2.33, and 2.35.
The –NH proton appeared as a broad singlet at d 13.20, and the –OH proton
appeared at d 14.47. The remaining spectral data confirmed the newly prepared
compounds’ structures (4a–k).
In conclusion, a novel, facile, one-pot, multicomponent reaction for the
synthesis of 4-(2-arylhydrazono)-1-(4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)
thiazol-2-yl)-3-methyl-1H-pyrazol-5(4H)-one is presented. The advantages of this
methodology are speed, good yield, simplicity, practicality, low cost, readily available
components, and easy workup.
EXPERIMENTAL
All the reagents and solvents were pure, purchased from commercial
sources, and used without further purification unless otherwise stated. 3-(2-
Bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one[26] and ethyl 2-(2-arylhydrazono)-
3-oxobutanoates[27] were prepared by the literature procedure. Melting points were
determined in open capillaries with a ‘‘Cintex’’ melting-point apparatus (Mumbai,
India) and were uncorrected. CHNS analysis was done by Carlo Erba EA 1108 auto-
matic elemental analyzer. The purity of the compounds was checked by thin-layer
chromatography (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 instru-
ment (SCIEX API-2000, ESI) at 12.5 eV.
General Procedure for the Synthesis of Compounds 4a–k
Compound 1 (1 mmol), thiosemicarbazide (1 mmol), and ethyl 2-(2-aryl-
hydrazono)-3-oxobutanoate (1.2 mmol) were in anhydrous ethanol (10 mL) and
heated at 80–85 ꢁC for 4 h. The product obtained was cooled, filtered, washed with
water, and recrystallized from anhydrous ethanol.
4-(2-Phenylhydrazono)-1-(4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-
yl)thiazol-2-yl)-3-methyl-1H-pyrazol-5(4H)-one (4a)
Orange-yellow solid; yield 86%; mp 287–289 ꢁC; IR (KBr, tmax): 1585 (-C N),
=
1
=
=
1660 (-C O, pyrazolone), 1700 (lactone -C O), 3375 (-NH), 3420 (-OH). H NMR
(400 MHz, DMSO-d6): d 2.26 (s, 3H, -CH3 of pyrone ring), 2.36 (s, 3H, CH3 of
pyrazolone), 6.25 (s, C5 of pyrone ring), 7.20–7.30 (m, 1H, -ArH), 7.40–7.50 (m,
2H, -ArH), 7.60–7.80 (m, 2H, -ArH), 7.90 (s, 1H, thiazole proton), 13.17 (s, 1H,
-NH), 14.23 (s, 1H, -OH). HRMS mass, calculated 409.08, found 408.0656. Anal. calcd.
for C19H15N5O4S: C, 55.74; H, 3.69; N, 17.11. Found: C, 55.70; H, 3.74; N, 17.17.
4-(2-p-Tolylhydrazono)-1-(4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-
yl)thiazol-2-yl)-3-methyl-1H-pyrazol-5(4H)-one (4b)
Light yellow solid; yield 82%; mp 273–275 ꢁC; IR (KBr, tmax): 1596 (-C N),
=
1
1676 (-C O, pyrazolone), 1694 (lactone -C O), 3374 (-NH), 3407 (-OH). H NMR
=
=

THIAZOLYL-PYRAZOLONES
3399
(400 MHz, DMSO-d6): d 2.26 (s, 3H, -CH3 of pyrone ring), 2.34 (s, 6H, CH3 of
pyrazolone and Ar-CH3), 6.27 (s, C5 of pyrone ring) 7.33 (d, 2H, J ¼ 8 -ArH), 7.67
(d, 2H, J ¼ 8 ArH), 7.90 (s, 1H, thiazole proton), 13.20 (s, 1H, -NH), 14.47 (s, 1H,
-OH). EI-MS 423 [M þ H]þ. Anal. calcd. for C20H17N5O4S: C, 56.73; H, 4.05; N,
16.54. Found: C, 56.79; H, 4.12; N, 16.59.
4-(2-o-Tolylhydrazono)-1-(4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-
yl)thiazol-2-yl)-3-methyl-1H-pyrazol-5(4H)-one (4c)
Orange-yellow solid; yield 80%; mp > 300 ꢁC; IR (KBr, tmax): 1543 (-C N),
=
=
=
1663 (-C O, pyrazolone), 1714 (lactone -C O), 3367 (-NH) and 3425 (-OH).
1H NMR (400 MHz, DMSO-d6): d 2.26 (s, 3H, -CH3 of pyrone ring), 2.38 (s, 3H,
Ar-CH3) 2.43 (s, 3H, CH3 of pyrazolone), 6.29 (s, C5 of pyrone ring), 7.20–7-40
(m, 3H, -ArH), 7.70–7.80 (m, 1H, -ArH), 7.90 (s, 1H, thiazole proton), 13.17 (s,
1H, -NH). EI-MS 423 [M þ H]þ. Anal. calcd. for C20H17N5O4S: C, 56.73; H, 4.05;
N, 16.54. Found: C, 56.78; H, 4.16; N, 16.59.
4-(2-(4-Nitrophenylhydrazono)-1-(4-(4-hydroxy-6-methyl-2-oxo-2H-
pyran-3-yl)thiazol-2-yl)-3-methyl-1H-pyrazol-5(4H)-one (4d)
Orange-yellow solid; yield 83%; mp 282–284 ꢁC; IR (KBr, tmax): 1607 (-C N),
=
1
=
=
1679 (-C O, pyrazolone), 1701 (lactone -C O), 3351 (-NH), 3397 (-OH). H NMR
(400 MHz, DMSO-d6): d 2.26 (s, 3H, CH3 of pyrone ring) 2.37 (s, 3H, CH3 of
pyrazolone), 6.28 (s, C5 of pyrone ring), 7.85–8.00 (m, 3H, -ArH), 8.20–8.40 (m,
2H, -1ArH and 1 thiazole proton), 13.30 (s, 1H, -NH), 14.40 (s, 1H, -OH). EI-MS
454 [M þ H]þ. Anal. calcd. for C19H14N6O6S: C, 50.22; H, 3.11; N, 18.49. Found:
C, 50.28; H, 3.16; N, 18.54.
4-(2-(3-Nitrophenylhydrazono)-1-(4-(4-hydroxy-6-methyl-2-oxo-2H-
pyran-3-yl)thiazol-2-yl)-3-methyl-1H-pyrazol-5(4H)-one (4e)
Yellow solid; yield 81%; mp 271–273 ꢁC; IR (KBr, tmax): 1594 (-C N), 1688
=
(-C O, pyrazolone), 1708 (lactone -C O), 3387 (-NH), 3398 (-OH). 1H NMR
(400 MHz, DMSO-d6): d 2.33 (s, 3H, -CH3 of pyrone ring), 2.42 (s, 3H, CH3 of pyr-
azolone), 6.27 (s, C5 of pyrone ring), 8.01–8.20 (m, 4H, -ArH), 8.51 (s, 1H, thiazole
proton), 13.26 (s, 1H, -NH), 14.41 (s, 1H, -OH). EI-MS 454 [M þ H]þ. Anal. calcd.
for C19H14N6O6S: C, 50.22; H, 3.11; N, 18.49. Found: C, 50.26; H, 3.15; N, 18.54.
=
=
4-(2-(2-Nitrophenylhydrazono)-1-(4-(4-hydroxy-6-methyl-2-oxo-2H-
pyran-3-yl)thiazol-2-yl)-3-methyl-1H-pyrazol-5(4H)-one (4f)
Orange-yellow solid; yield 78%; mp 294–296 ꢁC; IR (KBr, tmax): 1577 (-C N),
=
1
=
=
1678 (-C O, pyrazolone), 1704 (lactone -C O), 3395 (-NH), 3489 (-OH). H NMR
(400 MHz, DMSO-d6): d 2.27 (s, 3H, -CH3 of pyrone ring), 2.40 (s, 3H, CH3 of
pyrazolone), 6.23 (s, C5 of pyrone ring), 7.43–7.50 (m, 1H, -ArH), 7.90–8.00 (m, 2H,
-ArH), 8.10–8.20 (m, 1H, -ArH), 8.4 (s, 1H, thiazole proton), 14.23 (s, 1H, -NH),

3400
S. PENTA AND R. R. VEDULA
14.28 (s, 1H, -OH). EI-MS 454 [M þ H]þ. Anal. calcd. for C19H14N6O6S: C, 50.22; H,
3.11; N, 18.49. Found: C, 50.27; H, 3.15; N, 18.54.
4-(2-(2-Methoxyphenylhydrazono)-1-(4-(4-hydroxy-6-methyl-2-oxo-
2H-pyran-3-yl)thiazol-2-yl)-3-methyl-1H-pyrazol-5(4H)-one (4g)
Orange-yellow solid; yield 86%; mp > 300 ꢁC; IR (KBr, tmax): 1595 (-C N),
=
1
=
=
1678 (-C O, pyrazolone), 1704 (lactone -C O), 3357 (-NH), 3460 (-OH). H NMR
(400 MHz, DMSO-d6): d 2.26 (s, 3H, -CH3 of pyrone ring), 2.33 (s, 3H, CH3 of
pyrazolone), 3.99 (s, 3H, -OCH3), 6.29 (s, C5 of pyrone ring), 7.03–7.20 (m, 2H,
-ArH), 7.70–7.80 (m, 2H, -ArH), 7.9 (s, 1H, thiazole proton), 13.20 (s, 1H, -NH),
14.34 (s, 1H, -OH). EI-MS 439 [M þ H]þ. Anal. calcd. for C20H17N5O5S: C, 54.66;
H, 3.90; N, 15.94. Found: C, 54.69; H, 3.96; N, 15.98.
4-(2-(3-Methoxyphenylhydrazono)-1-(4-(4-hydroxy-6-methyl-2-oxo-
2H-pyran-3-yl)thiazol-2-yl)-3-methyl-1H-pyrazol-5(4H)-one (4h)
Orange-yellow solid; yield 76%; mp > 300 ꢁC; IR (KBr, tmax): 1595 (-C N),
=
1
=
=
1678 (-C O, pyrazolone), 1704 (lactone -C O), 3377 (-NH), 3411 (-OH). H NMR
(400 MHz, CDCl3): d 2.28 (s, 3H, -CH3 of pyrone ring), 2.41 (s, 3H, CH3 of pyrazo-
lone), 3.87 (s, 3H, -OCH3), 6.02 (s, C5 of pyrone ring), 6.82 (d, 1H, J ¼ 8 Hz, ArH),
7.02 (d, 2H, J ¼ 8 Hz, -ArH), 7.32 (t, 1H, J ¼ 8 Hz, -ArH), 7.96 (s, 1H, thiazole
proton), 13.22 (s, 1H, -NH), 14.39 (s, 1H, -OH). EI-MS 439 [M þ H]þ. Anal. calcd.
for C20H17N5O5S: C, 54.66; H, 3.90; N, 15.94. Found: C, 54.69; H, 3.95; N, 15.91.
4-(2-(4-Methoxyphenylhydrazono)-1-(4-(4-hydroxy-6-methyl-2-oxo-
2H-pyran-3-yl)thiazol-2-yl)-3-methyl-1H-pyrazol-5(4H)-one (4i)
Orange-yellow solid; yield 80%; mp > 300 ꢁC; IR (KBr, tmax): 1595 (-C N),
=
1
=
=
1678 (-C O, pyrazolone), 1707 (lactone -C O), 3367 (-NH), 3417 (-OH). H NMR
(400 MHz, DMSO-d6): d 2.26 (s, 3H, -CH3 of pyrone ring), 2.38 (s, 3H, CH3 of pyr-
azolone), 3.79 (s, 3H, -OCH3), 6.27 (s, C5 of pyrone ring), 6.90–7.10 (m, 3H, -ArH),
7.60–7.80 (m, 2H, 1-ArH and 1H of thiazole). EI-MS 439 [M þ H]þ. Anal. calcd. for
C20H17N5O5S: C, 54.66; H, 3.90; N, 15.94. Found: C, 54.61; H, 3.96; N, 15.98.
4-(2-(4-Chlorophenylhydrazono)-1-(4-(4-hydroxy-6-methyl-2-oxo-2H-
pyran-3-yl)thiazol-2-yl)-3-methyl-1H-pyrazol-5(4H)-one (4j)
Orange-yellow solid; yield 87%; mp 290–293 ꢁC; IR (KBr, tmax): 1557 (-C N),
=
1
=
=
1696 (-C O, pyrazolone), 1702 (lactone -C O), 3390 (-NH), 3407 (-OH). H NMR
(400 MHz, DMSO-d6): d 2.26 (s, 3H, -CH3 of pyrone ring), 2.35 (s, 3H, CH3 of pyr-
azolone), 6.28 (s, 1H, C5 of pyrone ring), 7.06 (d, 2H, -ArH), 7.07 (d, 2H, -ArH), 7.90
(s, 1H, thiazole proton), 13.07 (s, 1H, -NH), 14.38 (s, 1H, -OH). EI-MS 443 [M þ H]þ.
HRMS mass calculated 443.05; found, 444.0527. Anal. calcd. for C19H14ClN5O4S: C,
51.41; H, 3.18; N, 15.78. Found: C, 54.69; H, 3.94; N, 15.99.

THIAZOLYL-PYRAZOLONES
3401
2-(N’f1-[4-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)thiazol-2-yl)-3-
methyl-5-oxo-1,5-dihydro-pyrazol-4-ylideneg-hydrazino)-benzoic
Acid (4k)
Orange-yellow solid; yield 81%; mp > 300 ꢁC; IR (KBr, tmax): 1590 (-C N),
=
1
=
=
1677 (-C O, pyrazolone), 1710 (lactone -C O), 3357 (-NH), 3421 (-OH). H NMR
(400 MHz, DMSO-d6): d 2.25 (s, 3H, -CH3 of pyrone ring), 2.37 (s, 3H, CH3 of
pyrazolone), 6.26 (s, C5 of pyrone ring), 7.25 (d, 1H, J ¼ 8 Hz, ArH), 7.60–7.70 (m,
2H, -ArH), 7.90–8.10 (m, 2H, 1-ArH and 1H of thiazole), 14.52 (s, 1H, -NH),
14.73 (s, 1H, -COOH), 15.06 (s, 1H, -OH). EI-MS 453 [M þ H]þ. Anal. calcd. for
C20H15N5O6S: C, 52.98; H, 3.33; N, 15.45. Found: C, 15.95; H, 3.39; N 15.49.
ACKNOWLEDGMENT
The authors are thankful to the director, National Institute of Technology,
Warangal, A.P., India, for providing financial support and facilities.
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