Synthesis of some novel bioactive 4-oxy/thio substituted-1H-pyrazol-5(4H)-ones via efficient cross-Claisen condensation

Article abstract of DOI:10.1016/j.ejmech.2009.04.010

α-Oxy/thio substituted-β-keto esters were synthesized through an efficient cross-Claisen condensation of aryl oxy/thio acetic acid ethyl esters with acid chlorides, then it is converted in situ into 4-oxy/thio substituted-1H-pyrazol-5(4H)-ones by the addition of hydrazine or hydrazine derivatives and screened for their antibacterial, antifungal activities.

Full text of DOI:10.1016/j.ejmech.2009.04.010

European Journal of Medicinal Chemistry 44 (2009) 3852–3857
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of some novel bioactive 4-oxy/thio substituted-1H-pyrazol-
5(4H)-ones via efficient cross-Claisen condensation
,
,
c
R. Venkat Ragavan a b, V. Vijayakumar a , N. Suchetha Kumari
*
a Organic Chemistry Division, School of Science and Humanities, VIT University, Thiruvalam Road, Vellore 632 014, India
b Syngene International Pvt. Ltd., Biocon Park, Bangalore 560 099, India
c Department of Biochemistry, K.S. Hegde Medical Academy, Deralakatte 574162, India
a r t i c l e i n f o
a b s t r a c t
Article history:
a-Oxy/thio substituted-b-keto esters were synthesized through an efficient cross-Claisen condensation
Received 26 August 2008
Received in revised form
23 March 2009
Accepted 2 April 2009
Available online 14 April 2009
of aryl oxy/thio acetic acid ethyl esters with acid chlorides, then it is converted in situ into 4-oxy/thio
substituted-1H-pyrazol-5(4H)-ones by the addition of hydrazine or hydrazine derivatives and screened
for their antibacterial, antifungal activities.
Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords:
Cross-Claisen condensation
Substituted oxy/thio acetic acid ethyl esters
LiHMDS
Acid chloride
Hydrazine hydrate
4-Oxy/thio substituted-1H-pyrazol-5(4H)-
ones
Biological activity
1. Introduction
moiety and their antimicrobial evaluation. Almost all of the deriv-
atives showed good inhibition towards bacteria and fungi.
Pyrazolone derivatives have a broad spectrum of biological
activities being analgesic, antipyretic and anti-inflammatory ther-
apeutical drugs [1–3]. Pyrazolones are also well known elicitor of
hypersensitivity [4]. A class of new compounds with pyrazolone
moiety was synthesized and reported for their antibacterial, anti-
fungal activities by Al-Haiza et al. [5]. A new pyrazolone derivative,
edaravone (3-methyl-1-phenyl-2-pyrazoline-5-one) is being used
as a drug in clinical practice for brain ischemia [6,7] and also found
to be effective against myocardial ischemia [8]. Pyrazolone deriv-
atives such as antipyrine, aminopyrine and dipyrone are known as
antipyretic and analgesic substances [9] and their pharmacological
molecular mechanism has been widely surveyed. Some of the aryl
oxy pyrazolone derivatives are useful in the treatment of a variety
of disorders caused by Human Immunodeficiency Virus (HIV) and
other genetic ailments caused by retroviruses such as Acquired
Immune Deficiency Syndrome (AIDS) [10] (Fig. 1).
2. Results and discussion
2.1. Chemistry
The reaction of
b-keto esters with hydrazine or hydrazine
derivatives is the general and most prevalent method to synthe-
size pyrazolones [11–15]. To synthesize pyrazolones with oxygen
or sulphur linkage at the C-4 – indeed,
or sulphur linkage at the
methods to synthesis these
such as step-intensive, time consuming and usage of imidazoles.
Even though self-Claisen condensation method yields -keto
esters in single step, the main drawback is while varying substit-
uents [16–19]. However there are a few reports on the application
of cross-Claisen condensation between different esters or between
esters and acid chlorides [20–24]. A nucleophilic reaction of an
ester enolate with acid imidazolide has been widely used as
b
-keto esters with oxygen
-carbon are required. The reported
-keto esters have serious drawbacks
a
b
b
Herein we report the synthesis of novel pyrazolones, by intro-
ducing the oxygen or sulphur linkage at C-4 of the pyrazolone
a common method for synthesizing b-keto esters [25–28], but it
can be rather expensive to use imidazolide or active ester in
industrial setting. So we focused on the cross-Claisen
* Corresponding author. Tel.: þ91 9443916746.
E-mail address: kvpsvijayakumar@gmail.com (V. Vijayakumar).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.04.010

R. Venkat Ragavan et al. / European Journal of Medicinal Chemistry 44 (2009) 3852–3857
3853
H3C
H3C
H3C
N
N
N
N
N
N
H3C
H3C
H3C
O
N
N
H3C
O
O
CH
H3C
N
O
N
H3C
CH3
H3C
CH3
NaO3SH2C
Dipyrone
CH3
Aminopyrine
Isopropylantipyrine
Antipyrine
Fig. 1.
condensation between substituted oxy/thio acetic acid ethyl esters
and acid chlorides to improve the yield of -keto esters by
to their low nucleophilicity, but strong nucleophilic hydrazine like
methyl hydrazine reacted very well under these conditions. N-
substituted pyrazolones using comparatively less nucleophilic
hydrazines (1o–p) were synthesized in reasonable yield by two
steps (Method B). All the synthesized compounds were charac-
terised using 1H NMR, 13C NMR, LCMS and spectral data are given
in Experimental section.
b
changing the equivalence of base, acid chloride, time duration of
the reaction and the mode of additions. Finally yields were
improved to a greater extent in the generation of substituted aryl
oxy/thio acetic acid ethyl esters and are used in situ to synthesize
pyrazolones with oxygen or sulphur linkage at C-4 in one-pot by
the addition of hydrazine or hydrazine derivatives (Scheme 1).
Compounds 1a–n were prepared (by Method A) from corre-
sponding aryl oxy/thio acetic acid ethyl esters, which were
synthesized (see General procedure) from their respective
phenols, thiophenols, benzyl alcohol and mercaptan. When we
attempted to synthesize N-substituted pyrazolones surprisingly
substituted hydrazine like phenyl hydrazine, 4-iso-propyl phenyl
hydrazine did not react under these conditions, which may be due
2.2. Pharmacology
2.2.1. Antibacterial activity
We have investigated newly synthesized pyrazolones for
their antibacterial activity against Escherichia coli (ATTC-25922),
Staphylococcus aureus (ATTC-25923), Pseudomonas aeruginosa
(ATTC-27853) and Klebsiella pneumonia (recultured) bacterial
R3
COOC2H5
O
O
O
N
N
LiHMDS,-78°C
R3-NHNH2
Ethanol
+
X
R2
OC2H5
R2
O
Toluene
R2
Cl
R1
X
X
R1
Where
R1
X = O, S
1a-p
X
R1
R2
R3
1a
1b
1c
1d
1e
1f
O
O
O
O
S
-Ph
-Ph
-Ph
-CH2OPh
-CH2CH3
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-CH2OCH3
-CH3
-4-OCH3-Ph
-Ph
-CH3
S
-Ph
-CH2CH(CH3)2
-CH(CH3)2
-CH2CH(CH3)2
-CH3
1g
1h
1i
S
-Ph
S
-4-Cl-Ph
-CH2-3-Br-Ph
-CH2Ph
-CH2Ph
-Ph
O
S
1j
-CH2CH3
1k
1l
S
-CH2OCH3
-4-Cl-Ph
O
O
O
S
1m
1n
1o
1p
-Ph
-C(CH3)3
-Ph
-CH2CH(CH3)2
-CH2CH(CH3)2
-CH2CH3
-CH3
-Ph
-4-F-Ph
-4-F-Ph
O
-Ph
Scheme 1. Synthesis of 4-oxy/thio substituted pyrazolones via cross-Claisen condensation.

3854
R. Venkat Ragavan et al. / European Journal of Medicinal Chemistry 44 (2009) 3852–3857
Table 2
strains by the disc diffusion method [29,30]. The discs
measuring 6.25 mm in diameter were punched from Whatman
No. 1 filter paper. Batches of 100 discs were dispensed to each
screw-capped bottle and sterilized by dry heat at 140 ꢀC for an
hour. The test compounds were prepared with different
concentrations using Dimethylformamide (DMF). One milliliter
containing 100 times the amount of chemical in each disc was
added to each bottle, which contains 100 discs. The discs of
each concentration were placed in triplicate in a nutrient agar
medium separately seeded with fresh bacteria. The incubation
was carried out at 37 ꢀC for 24 h. Solvent and growth controls
were kept, the zones of inhibition and minimum inhibitory
concentrations (MIC) were noted. Results of these studies are
given in Table 1, and compared with the standard ciprofloxacin.
Interestingly almost all these compounds exhibited good anti-
bacterial activity. Among the compounds, 1a, 1f, 1b, 1j, 1g and
1m showed good inhibition towards all the four bacteria tested.
The structure–activity relationship studies reveal that the
compounds with aliphatic substituent at C-3 and free NH at N-1
(1a, 1b, 1f, 1g, 1j and 1m) are very much active, the presence of
methoxyl group either at aryl ring or alkyl chain reduces the
antibacterial activity. Nitrogen substituted pyrazolones (either
aryl or alkyl) also showed very good antibacterial activity
towards S. aureus, P. aeruginosa and K. pneumonia but these
nitrogen substituted pyrazolones are moderately active against
E. coli. Aryl substituent at C-3 of the pyrazolones reduces the
antibacterial activity against P. aeruginosa, K. pneumonia and
moderately active against E. coli and active against S. aureus.
Since almost all the compounds are effective, there is a need for
further studies.
Antifungal activities of the compounds 1a–p (Zone of inhibition in mm, MIC in
mg/ml given in parenthesis).
Product
Trichophyton
Penicillium
A. flavus
A. fumigates
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
19 (6.25)
16 (6.25)
17 (6.25)
<10 (50)
18 (6.25)
21 (6.25)
16 (6.25)
19 (6.25)
20 (6.25)
17 (6.25)
<10 (50)
<10 (50)
19 (6.25)
18 (6.25)
18 (6.25)
21 (6.25)
27 (3.125)
18 (6.25)
18 (6.25)
17 (6.25)
<10 (50)
21 (6.25)
18 (6.25)
19 (6.25)
20 (6.25)
18 (6.25)
19 (6.25)
<10 (50)
<10 (50)
21 (6.25)
19 (6.25)
19 (6.25)
17 (6.25)
23 (6.25)
20 (6.25)
21 (6.25)
18 (6.25)
<10 (50)
16 (6.25)
18 (6.25)
18 (6.25)
18 (6.25)
19 (6.25)
17 (6.25)
<10 (50)
<10 (50)
16 (6.25)
18 (6.25)
20 (6.25)
19 (6.25)
27 (3.125)
21 (6.25)
17 (6.25)
20 (6.25)
<10 (50)
17 (6.25)
18 (6.25)
20 (6.25)
17 (6.25)
18 (6.25)
17 (6.25)
<10 (50)
<10 (50)
18 (6.25)
16 (6.25)
19 (6.25)
21 (6.25)
26 (6.25)
Ciclopiroxolamine
decanted and the plates were dried by placing them in an incu-
bator at 37 ꢀC for 1 h. Using an agar punch, wells were made on
these seeded agar plates, and 10–50 mg/ml of the test compounds
in DMSO was added into each well with labelling. A control was
also prepared for plates in the same way using solvent DMSO. The
Petri dishes were prepared in triplicate and maintained at 37 ꢀC
for 3–4 days. Antifungal activity was determined by measuring
the inhibition zone. The results of these studies are given in Table 2
and compared with the standard Ciclopiroxolamine. Almost all
these synthesized pyrazolones showed good activity against all
the fungi tested. Particularly compounds 1a–c, 1e–g, 1i, 1j and
1m–p were active against all the above fungi. The structure–
activity relationship studies revealed that aliphatic substituent at
C-3, aryl oxy/aryl thio at C-4, either substituted or free NH at N-1
may be the cause for their effectiveness against these fungi. On the
other hand the methoxy substituent either at aryl ring or alkyl
chains is not found to be effective against these organisms even at
the higher concentrations.
2.2.2. Antifungal activity
Newly synthesized pyrazolones were screened for their anti-
fungal activity against Aspergillus flavus (NCIM No. 524), Asper-
gillus fumigates (NCIM No. 902), Candida albicans (NCIM No. 3100),
Penicillium marneffei (recultured) and Trichophyton menta-
grophytes (recultured) in DMSO by serial plate dilution method
[16–18]. Sabouraud’s agar media were prepared by dissolving
peptone (1 g),
D-glucose (4 g) and agar (2 g) in distilled water
(100 ml) and the pH was adjusted to 5.7. Normal saline was used
to make a suspension of spores of fungal strain for lawning. A
loopful of particular fungal strain was transferred to 3 ml of saline
to get a suspension of corresponding species. 20 ml of agar media
was poured into each Petri dish. An excess of suspension was
3. Conclusion
A series of novel pyrazolones having aryl oxy/thio substituent at
the C-4 position were synthesized through efficient cross-Claisen
condensation and screened for their biological activities. Almost all
compounds showed good activity against all the bacteria and fungi
tested. Compounds 1a, 1b, 1f, 1g, 1j and 1m showed the best
activities against all the bacteria tested. Compounds 1a–c, 1e–g, 1i,
1j and 1m–p showed very good activity against all the fungi tested.
Alkyl groups at the C-3 of the pyrazolones increased their biological
activities, but on the other hand aryl substituent at C-3 decreased
their biological activities.
Table 1
Antibacterial activities of the compounds 1a–p (zone of inhibition in mm, MIC in
mg/ml given in parenthesis).
Product
S. aureus
E. coli
17 (6.25)
18 (6.25)
12 (25)
11 (25)
13 (25)
21 (6.25)
18 (6.25)
11 (25)
P. aeruginosa
Klebsiella sp.
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
18 (6.25)
19 (6.25)
17 (6.25)
19 (6.25)
18 (6.25)
19 (6.25)
20 (6.25)
18 (6.25)
21 (6.25)
16 (6.25)
17 (6.25)
21 (6.25)
16 (6.25)
19 (6.25)
19 (6.25)
16 (6.25)
23 (6.25)
16 (6.25)
20 (6.25)
17 (6.25)
<10 (50)
19 (6.25)
18 (6.25)
17 (6.25)
17 (6.25)
18 (6.25)
20 (6.25)
<10 (50)
<10 (50)
20 (6.25)
19 (6.25)
20 (6.25)
18 (6.25)
28 (6.25)
19 (6.25)
16 (6.25)
20 (6.25)
<10 (50)
16 (6.25)
21 (6.25)
16 (6.25)
16 (6.25)
19 (6.25)
17 (6.25)
<10 (50)
<10 (50)
18 (6.25)
17 (6.25)
19 (6.25)
20 (6.25)
24 (6.25)
4. Experimental
4.1. General
11 (25)
All reagents were purchased from Aldrich and used as
received. LiHMDS solutions were kept under nitrogen atmo-
sphere after opening. Acid chlorides were freshly prepared and
used. Dry toluene, acetic acid and ethanol were supplied by
Spectrochem. All chemistry was performed under a nitrogen
atmosphere using standard techniques. Melting points were
determined by Buchi B-545 apparatus. All the NMR spectra
were measured using either Bruker AMX 400 or Bruker DPX
17 (6.25)
<10 (50)
12 (25)
18 (6.25)
12 (25)
13 (25)
14 (25)
32 (6.25)
Ciprofloxacin

R. Venkat Ragavan et al. / European Journal of Medicinal Chemistry 44 (2009) 3852–3857
3855
300 instrument with 5 mm PABBO BB-1H tubes. 1H NMR
spectra were measured for approximately 0.03 M solutions in
d6-DMSO at 300 MHz or 400 MHz with TMS as internal refer-
ence. 13C NMR spectra were measured for approximately 0.05 M
solutions in d6-DMSO at 75 MHz or 100 MHz with TMS as
internal reference. In all the cases pyrazolone was recorded in
the enol form. LCMS were obtained using Agilent 1200 series LC
and Micromass zQ spectrometer. Column chromatography was
performed using a Silica gel (230–400 mesh).
2H), 1.03 (t, J ¼ 15.2 Hz, 3H); 13C NMR (75 MHz, d6-DMSO):
d
159.3,
152.9, 136.2, 130.2, 121.8, 119.9, 115.1, 17.4, 13.0; MS calcd. for
C11H12N2O2: 204.22. Found: 205.3 (M þ 1).
4.4.3. 3-Methoxymethyl-4-phenoxy-1H-pyrazol-5(4H)-one (1c)
Purified by column chromatography (Methanol:Ethyl acetate,
1:99), pale yellow solid, 41% yield, m.p. 145.8–146.8 ꢀC, 1H NMR
(400 MHz, d6-DMSO):
J ¼ 7.40 Hz, 2H), 6.97 (t, J ¼ 7.32 Hz, 1H), 6.87 (d, J ¼ 8.60 Hz, 2H),
4.16 (s, 2H), 3.15 (s, 3H); 13C NMR (75 MHz d6-DMSO):
d
¼ 11.70 (br s, 1H), 9.80 (br s, 1H), 7.27 (t,
d
¼ 159.1,
4.2. General procedure to synthesize aryl oxy/thio acetic acid ethyl
152.3, 131.3, 129.7, 122.0, 121.3, 115.2, 62.8, 57.76. MS calcd. for
esters (except 1i–k)
C11H12N2O3: 220.22. Found: 221.1 (M þ 1).
To the solution of phenol (10 mmol) in DMF (20 ml), anhydrous
K2CO3 (20 mmol) was added at room temperature (RT). After
10 minutes ethyl bromo acetate (10 mmol) was added and stirred at
RT overnight. Reaction was monitored by TLC, reaction mixture was
filtered through celite and the filtrate was concentrated to get the
aryl oxy/thio acetic acid ethyl esters in good yield.
4.4.4. 4-(4-Methoxyphenoxy)-3-methyl)-1H-pyrazol-5(4H)-one (1d)
Purified by column chromatography (Methanol:Ethyl acetate,
1:99), white solid, 47% yield, m.p. 200.6–201.5 ꢀC, 1H NMR
(300 MHz, d6-DMSO):
J ¼ 7.21 Hz, 2H), 6.80 (d, J ¼ 6.72 Hz, 2H), 3.67 (s, 3H), 1.90 (s, 3H);
13C NMR (75 MHz, d6-DMSO):
d
¼ 11.20 (br s, 1H), 9.70 (br s, 1H), 6.25 (d,
d
¼ 154.4, 153.1, 152.9, 130.7, 121.4,
116.0, 114.9, 55.8, 9.26. MS calcd. for C11H12N2O3: 220.22. Found:
220.9 (Mþ).
4.3. General procedure to synthesize benzyl oxy/thio acetic acid
ethyl esters (for 1i–k)
4.4.5. 3-Methyl-4-(phenylthio)-1H-pyrazol-5(4H)-one (1e)
Purified by column chromatography (Methanol:Ethyl acetate,
1:9), white solid 45% yield, m.p. 292.5–293.8 ꢀC, 1H NMR
To the solution of benzyl alcohol or mercaptan (10 mmol) in
DMF (20 ml), sodium hydride (12 mmol, 60% in mineral oil) was
added in portions at 0 ꢀC then stirred for 30 minutes in the same
temperature. Ethyl bromo acetate (12 mmol) was added slowly at
0 ꢀC and stirred at RT for 2 h. Reaction was monitored by TLC, and
the reaction mixture was quenched with saturated NH4Cl (20 ml),
extracted with ethyl acetate (2 ꢁ 100 ml), the combined organic
layer was washed with water (2 ꢁ 20 ml), brine solution
(1 ꢁ 20 ml), dried over Na2SO4 and evaporated to dryness. Crude
was purified by column chromatography (15% Ethyl acetate in Pet.
ether) to get the product in good yield.
(300 MHz, d6-DMSO)
d
¼ 10.00 (br s, 1H), 7.22 (t, J ¼ 7.65 Hz, 2H),
7.06 (t, J ¼ 7.53 Hz, 1H), 6.96 (d, J ¼ 8.25 Hz, 2H), 2.08 (s, 3H); 13C
NMR (100 MHz, d6-DMSO):
125.1, 87.3, 10.7. MS calcd. for C10H10N2OS: 206.2. Found: 206.9
(Mþ).
d
¼ 162.7, 145.0, 139.5, 129.3, 125.2,
4.4.6. 3-Isobutyl-4-phenylthio-1H-pyrazol-5(4H)-one (1f)
Purified by column chromatography (Pet. Ether:Ethyl acetate,
1:1), white solid, 51% yield, m.p. 198.7–199.9 ꢀC, 1H NMR (400 MHz,
d6-DMSO):
d
¼ 12.00 (br s, 1H), 10 (br s, 1H), 7.22 (t, J ¼ 7.60 Hz, 2H),
4.4. General procedure to synthesize 4-aryl oxy/thio-1H-pyrazol-
5(4H)-ones (Method A)
7.07 (t, J ¼ 7.20 Hz, 1H), 6.97 (d, J ¼ 7.60 Hz, 2H), 2.36 (d, J ¼ 7.60 Hz,
2H), 1.85 (m, 1H), 0.90 (d, J ¼ 4.40 Hz, 6H); 13C NMR (100 MHz, d6-
DMSO):
d
¼ 162.8, 147.9, 139.7, 129.1, 125.2, 124.9, 87.5, 34.2, 28.2,
LiHMDS (11 mmol, 1 M solution in THF) was added quickly via
syringe to the solution of an ester (5.5 mmol) in toluene (15 ml) at
ꢂ30 ꢀC with stirring and the formed anion was allowed to stand
approximately for 2 minutes then acid chloride (6.9 mmol) was
added in one portion with stirring. Reaction mixture (RM) was
removed from acetone–dry ice bath and the stirring continued for
10 minutes at RT, then 2 ml of acetic acid, followed by 15 ml of
ethanol and hydrazine hydrate (44 mmol) were added and refluxed
for 10 minutes. Then the RM was concentrated under reduced
pressure, the resulting solid was dissolved in ethyl acetate, washed
with brine solution, dried over Na2SO4 and evaporated to dryness.
See specific compounds for purification details. (Methyl hydrazine
was used in place of hydrazine hydrate in the preparation of
compound 1n.)
22.6. IR (cmꢂ1) 3061, 2954, 2866, 2591, 1590. MS calcd. for
C13H16N2OS: 248.35. Found: 248.9 (Mþ).
4.4.7. 3-Isopropyl-4-phenylthio-1H-pyrazol-5(4H)-one (1g)
Purified by column chromatography (Pet. Ether:Ethyl acetate,
1:1), white solid, 49% yield, m.p. 216.7–217.9 ꢀC, 1H NMR (400 MHz,
d6-DMSO):
d
¼ 12.00 (br s, 1H), 10.00 (br s, 1H), 7.23 (t, J ¼ 7.60 Hz,
2H), 7.07 (t, J ¼ 7.20 Hz, 1H), 6.97 (d, J ¼ 7.60 Hz, 2H), 2.96 (m, 1H),
1.15 (d, J ¼ 9.60, 6H); 13C NMR (100 MHz, d6-DMSO):
d
¼ 162.8,
154.0, 139.8, 129.2, 125.1, 125.0, 85.6, 25.8, 21.9. MS calcd. for
C12H14N2OS: 234.3. Found: 232.80 (Mꢂ).
4.4.8. 4-(4-Chlorophenylthio)-3-isobutyl-1H-pyrazol-5(4H)-one (1h)
Purified by column chromatography (Pet. ether:Ethyl
acetate, 1:1), yellow solid, 53% yield, m.p. 227.8–228.9 ꢀC, 1H
4.4.1. 3-(Benzyloxy)-4-phenoxy-1H-pyrazol-5(4H)-one (1a)
Purified by recrystallisation using ethanol as solvent, pale
yellow solid, 89% yield, m.p. 173.8–175.1 ꢀC, 1H NMR (400 MHz, d6-
NMR (400 MHz, d6-DMSO):
d
¼ 12.00 (br s, 1H), 10.00 (br s, 1H),
7.29 (d, J ¼ 8.40 Hz, 2H), 6.98 (d, J ¼ 6.80 Hz, 2H), 2.36
(d, 6.80 Hz, 2H), 1.85 (m, 1H), 0.78 (d, J ¼ 6.40 Hz, 6H); 13C NMR
DMSO):
d
12 (br s,1H), 10 (br s, 1H), 7.22 (m, 4H), 6.88 (m, 6H),
(100 MHz, d6-DMSO) d 162.7, 147.9, 138.9, 129.5, 129.1, 126.8,
4.81(s, 2H), 13C NMR (400 MHz, d6-DMSO):
d
159.0, 158.3, 129.8,
87.1, 34.2, 28.2, 22.6. MS calcd. for C13H15ClN2OS: 282.8. Found:
129.8, 122.2, 121.4, 115.4, 115.0, 59.2.
283.0 (Mþ).
4.4.2. 3-Ethyl-4-phenoxy-1H-pyrazol-5(4H)-one (1b)
4.4.9. 4-(3-Bromobenzyloxy)-3-methyl-1H-pyrazol-5(4H)-one (1i)
Purified by column chromatography (Methanol:Ethyl acetate,
1:99), white solid, 40% yield, m.p. 182.9–184.0 ꢀC, 1H NMR
Purified by column chromatography (Acetone: ethyl acetate,
1:4), white solid, 42% yield, m.p. 195.3–196.8 ꢀC, 1H NMR (400 MHz,
d6-DMSO):
d
11.3 (s, 1H), 9.7 (s, 1H), 7.27 (t, J ¼ 15.5 Hz, 2H), 6.96
(400 MHz, d6-DMSO):
(s, 1H), 7.50 (d, J ¼ 5.91 Hz, 1H), 7.37 (d, J ¼ 5.76 Hz, 1H), 7.31
d
¼ 10.80 (br s, 1H), 9.60 (br s, 1H), 7.57
(t, J ¼ 15.28 Hz, 1H), 6.84 (d, J ¼ 8.56 Hz, 2H), 2.35 (q, J ¼ 22.8 Hz,

3856
R. Venkat Ragavan et al. / European Journal of Medicinal Chemistry 44 (2009) 3852–3857
(t, J ¼ 7.72 Hz, 1H), 4.81 (s, 2H), 1.90 (s, 3H); 13C NMR (75 MHz. d6-
mixture was concentrated to dryness. See specific compounds for
purification details.
DMSO):
d
¼ 152.8, 141.2, 131.0, 130.9, 130.85, 129.4, 127.4, 125.12,
121.9, 73.9, 9.2. Found: 282.498 and 284.495. MS calcd. for
C11H11BrN2O2: 283.12. Found: 284.8 (M þ 1).
4.5.1. 1-(4-Fluorophenyl)-3-isobutyl-4-phenylthio-1H-pyrazol-
5(4H)-one (1o)
4.4.10. 4-(Benzylthio)-3-ethyl-1H-pyrazol-5(4H)-one (1j)
Purified by column chromatography (30% Ethyl acetate in Pet.
Purified by column chromatography (Methanol:Ethyl acetate,
ether), white solid, 38% yield, m.p. 220.4–221.3 ꢀC, 1H NMR
1:9), off-white solid, 41% yield, m.p. 227.3–228.8 ꢀC, 1H NMR
(400 MHz, d6-DMSO):
d
¼ 12.20 (br s, 1H), 7.75 (d, J ¼ 8.52 Hz, 2H),
(400 MHz, d6-DMSO):
d
¼ 11.50 (br s, 1H), 9.80 (br s, 1H), 7.25–7.08
7.28 (m, 4H), 7.08 (m, 3H), 2.35 (d, J ¼ 3.08 Hz, 2H), 1.92 (m, 1H),
(m, 3H), 7.07 (d, J ¼ 6.64 Hz, 2H), 3.66 (s, 2H), 2.10 (q, J ¼ 8.00 Hz,
0.84 (d, J ¼ 6.56 Hz, 6H); 13C NMR (400 MHz, d6-DMSO):
¼ 161.5,
d
2H), 0.84 (t, J ¼ 7.60 Hz, 3H); 13C NMR (100 MHz, d6-DMSO):
159.1, 155.0, 139.0, 135.2, 129.4, 125.4, 125.3, 123.5, 116.3, 116.1,
55.4, 36.1, 27.8, 22.8. MS calcd. for C19H19FN2O2: 320.36. Found:
320.8 (Mþ).
d
¼ 162.5, 149.4, 139.1, 129.2, 128.4, 126.9, 89.4, 18.1, 13.3. MS calcd.
for C12H14N2OS: 234.3. Found: 234.9 (Mþ).
4.4.11. 4-(Benzylthio)-3-methoxymethyl-1H-pyrazol-5(4H)-one (1k)
Purified by column chromatography (Pet. ether:Ethyl
acetate, 1:1), pale yellow solid, 41% yield, m.p. 114.4–115.7 ꢀC,
4.5.2. 3-Ethyl-1-(4-fluorophenyl)-4-phenoxy-1H-pyrazol-5(4H)-
one (1p)
Purified by column chromatography (30% ethyl acetate in Pet.
1H NMR (400 MHz, d6-DMSO):
d
¼ 7.31–717 (m, 3H), 7.07 (d,
ether), white solid, 39% yield, m.p. 168.8 ꢀC, 1H NMR (400 MHz, d6-
J ¼ 7.60 Hz, 2H), 3.79 (s, 2H), 3.69 (s, 2H), 3.13 (s, 3H); 13C NMR
DMSO):
d
¼ 11.58 (br s, 1H), 7.75 (d, J ¼ 8.80 Hz, 2H), 7.32 (t,
(100 MHz, CD3OD):
d
¼ 164.3, 148.3, 140.7, 130.7, 129.7, 128.3,
J ¼ 7.20 Hz, 3H), 7.00 (m, 3H), 2.34 (br s, 2H), 1.60 (br s, 3H); 13C
93.1, 65.7, 59.0, 41.3. MS calcd. for C12H14N2O2S: 250.32. Found:
251.0 (Mþ).
NMR (400 MHz, d6-DMSO):
122.3, 119.2, 166.2, 116.0, 115.5, 115.2, 19.8, 12.5. MS calcd. for
C17H15FN2O2: 298.31. Found: 298.6 (Mþ).
d
¼ 158.8, 146.3, 135.9, 130.1, 123.1,
4.4.12. 3-(4-Chlorophenyl)-4-phenoxy-1H-pyrazol-5(4H)-one (1l)
Purified by column chromatography (Methanol:Ethyl acetate,
1:99), pale yellow solid, 40% yield, m.p. 207.5–208.6 ꢀC, 1H NMR
Acknowledgements
(300 MHz, d6-DMSO):
d
¼ 12.20 (br s, 1H), 10.10 (br s, 1H), 7.63 (d,
Authors are grateful to Syngene International Pvt. Ltd.,
(Dr. Goutham Das and Dr. P. Sathya shanker) for their invaluable
support.
J ¼ 8.25 Hz, 2H), 7.45 (d, J ¼ 10.68 Hz, 2H), 7.28 (t, J ¼ 8.04 Hz, 2H),
6.98 (t, J ¼ 7.53 Hz, 1H), 6.91(d, J ¼ 7.74 Hz, 2H); 13C NMR (75 MHz,
d6-DMSO):
C15H11ClN2O2: 286.71. Found: 287.2.
d
¼ 158.3, 132.8, 130.1, 129.4, 126.8, 122.4. MS calcd. for
Appendix. Supplementary data
4.4.13. 3-Tert-butyl-4-phenoxy-1H-pyrazol-5(4H)-one (1m)
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.ejmech.2009.04.010.
Purified by preparative HPLC, brown solid, 39% yield, m.p.
233.3–234.6 ꢀC, 1H NMR (300 MHz, d6-DMSO):
d
¼ 10.00 (br s, 2H),
7.26 (t, J ¼ 7.44 Hz, 2H), 6.94 (t, J ¼ 6.96 Hz, 1H), 6.83 (d, J ¼ 7.53 Hz,
2H), 1.16 (s, 9H); 13C NMR (75 MHz, d6-DMSO):
References
d
¼ 159.0, 153.1,
142.7, 129.8, 121.8, 119.0, 115.1, 31.7, 29.2. MS calcd. for C13H16N2O2:
[1] R.N. Brogden, Pyrazolone derivatives, Drugs 32 (1986) 60–70.
[2] C. Coersmeier, H.R. Wittenberg, U. Aehringhaus, K.W. Dreyling, B.M. Peskar,
K. Brune, B.A. Pesker, Agents Actions Suppl. 19 (1986) 137–153.
[3] A. Gursoy, S. Demirayak, G. Capan, K. Erol, K. Vural, Eur. J. Med. Chem. 35
(2000) 359–364.
232.27. Found: 233.3 (M þ 1).
4.4.14. 3-Isobutyl-1-methyl-4-phenoxy-1H-pyrazol-5(4H)-one (1n)
Purified by column chromatography (Methanol:Dichloro-
methane, 2:98) pale brown solid, 41% yield, m.p. 141.2–141.9 ꢀC,
[4] M. Levy, Thorax 55 (2000) 72–74.
[5] M.A. Al-Haiza, S.A. El-Assiery, G.H. Sayed, Acta Pharm. 51 (2001) 251–261.
[6] T. Watanabe, S. Yuki, M. Egawa, H. Nishi, J. Pharmacol. Exp. Ther. 268 (1984)
1597–1604.
[7] H. Kawai, H. Nakai, M. Suga, S. Yuki, T. Watanabe, K.I. Saito, J. Pharmcol. Exp.
Ther. 281 (1997) 921–927.
[8] T.W. Wu, L.H. Zeng, J. Wu, K.P. Fung, Life Sci. 71 (2002) 2249–2255.
[9] M. Himly, B. Jahn-Schmid, K. Pittertschatscher, B. Bohle, K. Grubmayr,
F. Ferreira, H. Ebner, C. Ebner, J. Allergy Clin. Immunol. 111 (2003) 882–888.
[10] O. Barba, L.H. Jones, WO Patent 029042 A1, 2004.
[11] S.P. Hiremath, A.R. Saundane, B.H.M. Mruthyunjayaswamy, J. Heterocycl.
Chem. 30 (1993) 603–609.
[12] K.J. Duffy, M.G. Darcy, E. Delorme, S.B. Dillon, D.F. Eppley, C.E. Miller, L. Giampa,
C.B. Hopson, Y. Huang, R.M. Keenan, P. Lamb, L. Leong, N. Liu, S.G. Miller,
A.T. Price, J. Rosen, T.N. Shaw, H. Smith, K.C. Stark, S.S. Tain, C. Tyree,
K.J. Wiggall, L. Zhang, J.I. Luengo, J. Med. Chem. 44 (2001) 3730–3745.
[13] F.M. Jonathan, J.B. David, C. Kelvin, P.M. John, H.S. Mark, J. Med. Chem. 38
(1995) 3524–3535.
[14] E.K. Darin, R.B. Miller, J.K. Mark, Tetrahedron Lett. 40 (1999) 3535–3538.
[15] M. Janja, S. Vinko, Heterocycles 41 (1995) 1207–1218.
[16] H. Adkins, R.M. Elofson, A.G. Rossow, C.C. Robinson, J. Am. Chem. Soc. 71
(1949) 3622–3629.
[17] D.D. Pratt, R. Robinson, J. Chem. Soc., Trans. 127 (1925) 166–175.
[18] S. Gerhard, W. Anna, US Patent 4447444, 1984.
[19] J.M. Petersen, C.R. Hauser, J. Am. Chem. Soc. 71 (1949) 770–773.
[20] S. Ohta, A. Shimabayashi, S. Hayakawa, M. Sumino, M. Okamoto, Synthesis
(1985) 45–47.
1H NMR (400 MHz, CD3OD):
d
¼ 7.27 (t, J ¼ 7.48 Hz, 2H), 6.97 (t,
J ¼ 7.32 Hz, 1H), 6.92 (d, J ¼ 7.60 Hz, 2H), 3.48 (s, 3H), 2.31 (d,
J ¼ 7.28 Hz, 2H), 1.89 (m, 1H), 0.96 (d, J ¼ 6.28 Hz, 6H); 13C NMR
(100 MHz, CD3OD):
32.0, 29.2, 22.0. MS calcd. for C14H18N2O2: 246.305. Found:
247.0 (Mþ).
d
¼ 160.2, 142.7, 130.8, 123.4, 116.3, 34.9,
4.5. General procedure to synthesize N-substituted-4-aryl oxy/thio-2,
4-dihydro-pyrazol-3-ones (Method B)
LiHMDS (11 mmol, 1 M solution in THF) was added quickly via
syringe to the solution of an ester (5.5 mmol) in toluene (15 ml) at
ꢂ30 ꢀC with stirring and thus formed anion was allowed to stand
approximately for 2 minutes then acid chloride (6.9 mmol) was
added in one portion while stirring. Reaction mixture was removed
from acetone–dry ice bath and continues the stirring for
10 minutes, then quenched with water and extracted with ethyl
acetate (2 ꢁ 100 ml) and the combined organic layer was dried over
anhydrous Na2SO4, concentrated on rotary evaporator. The above
crude was taken in the mixture of ethanol (20 ml) and acetic acid
(2 ml), to this substituted hydrazine (10 mmol) was added and
refluxed overnight. Reaction was monitored by TLC, reaction
[21] N.S. Trotter, S. Takahashi, T. Nakata, Org. Lett. 1 (1999) 957–959.
[22] C. Spino, N. Mayes, H. Desfosses, Tetrahedron Lett. 37 (1996) 6503–6506.
[23] T. Nakata, T. Komatsu, K. Nagasawa, Chem. Pharm. Bull. 42 (1994)
2403–2405.

R. Venkat Ragavan et al. / European Journal of Medicinal Chemistry 44 (2009) 3852–3857
3857
[24] L. Shao, T. Seki, H. Kawano, M. Saburi, Tetrahedron Lett. 32 (1991)
7699–7702.
[28] A. Ino, Y. Hasegawa, A. Murabayashi, Tetrahedron Lett. 39 (1998)
3509–3512.
[25] R.V. Hoffman, J. Tao, Tetrahedron 53 (1997) 7119–7126.
[26] J. Tao, R.V. Hoffman, J. Org. Chem. 62 (1997) 6240–6244.
[27] P. Jouin, M.N. Dufour, I. Maugras, A. Pantaloni, B. Castro, Tetrahedron Lett. 29
(1988) 2661–2664.
[29] K.K. Vijaya Raj, B. Narayana, B.V. Ashalatha, N. Suchetha Kumari, B.K. Sarojini,
Eur. J. Med. Chem. 42 (2007) 425–429 and references citied therein.
[30] B.A. Arthington, M. Motley, D.W. Warnock, C.J. Morrison, J. Clin. Microbiol. 38
(2000) 2254–2260.