A novel route to 4-oxy/thio substituted-1H-pyrazol-5(4H)-ones via efficient cross-Claisen condensation

Article abstract of DOI:10.1002/jhet.558

α-Oxy/thio substituted β-keto esters were synthesized through an efficient cross-Claisen condensation of oxy/thio substituted acetic acid ethyl esters with acid chlorides, which in turn converted in situ into 4-oxy/thio substituted-1H-pyrazol-5(4H)-ones by the addition of hydrazine and its derivatives. This method has been found to be extremely fast, general, and useful toward the synthesis of inaccessible pyrazolones and synthetically demanding 4-oxy/thio substituted pyrazolones.

Full text of DOI:10.1002/jhet.558

March 2011
A Novel Route to 4-Oxy/thio substituted-1H-pyrazol-5(4H)-
ones via Efficient Cross-Claisen Condensation
323
R. Venkat Ragavan and V. Vijayakumar*
Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632014,
Tamilnadu, India
*E-mail: kvpsvijayakumar@gmail.com
Received March 7, 2010
DOI 10.1002/jhet.558
Published online 10 December 2010 in Wiley Online Library (wileyonlinelibrary.com).
a-Oxy/thio substituted b-keto esters were synthesized through an efficient cross-Claisen condensation
of oxy/thio substituted acetic acid ethyl esters with acid chlorides, which in turn converted in situ into
4-oxy/thio substituted-1H-pyrazol-5(4H)-ones by the addition of hydrazine and its derivatives. This
method has been found to be extremely fast, general, and useful toward the synthesis of inaccessible
pyrazolones and synthetically demanding 4-oxy/thio substituted pyrazolones.
J. Heterocyclic Chem., 48, 323 (2011).
INTRODUCTION
develop an efficient procedure for cross-Claisen
condensation.
A considerable interest has been shown to develop
new methods for the synthesis of heterocyclic systems.
Particularly, 2,3-pyrazol-1(5H)-ones have been reported
as pharmaceuticals and useful intermediates in the syn-
thesis of heterocycles [1,2]. Some of the aryloxy pyrazo-
lone derivatives are in clinical practice for the treatment
of a variety of disorders caused by human immunodefi-
ciency virus and other genetic ailments caused by retro-
viruses such as acquired immune deficiency syndrome
[3]. To date, synthesis of these compounds have been
somewhat limited by the available chemistry. The reac-
tion of b-keto esters with hydrazine and its derivatives
is a general and most prevalent method to obtain pyra-
zolones [4], other synthetic methods which do not
require b-keto esters have also been reported [5], but
these methods tend to have serious drawbacks such as
step intensive, usage of sensitive palladium catalysts,
and carbon monoxide. So these factors confer that
usage of b-keto esters as an intermediate is the broadest
and most efficient way to synthesize pyrazolones.
To synthesize 4-oxy/thio substituted pyrazolones indeed,
a-oxy/thio substituted b-keto esters are still in need.
The reported methods to synthesize a-oxy/thio substi-
tuted b-keto esters have serious drawbacks such as
step intensive, time consuming, and usage of imidazoles
[6]. There is a single-step reaction protocol for the self-
Claisen condensation [7], which has main limitation
in varying the substituents. Hence, there is a need to
RESULTS AND DISCUSSION
This work focused on the cross-Claisen condensation
between oxy/thio substituted acetic acid ethyl ester and
acid chlorides. We hypothesized that an ester enolate
might react in a smooth manner with strong electrophile
acid chloride, if proper conditions have maintained to
slow down the side reactions such as, self-Claisen con-
densation and O-alkylation. However, there have been
very few reports on the application of cross-Claisen con-
densation between different esters [8] or between esters
and acid chlorides, and some successful results were
also been reported in the reactions using hydroxyl esters
[9]. A nucleophilic reaction of an ester enolate with acid
imidazolide has been widely used to synthesis b-keto
esters [10], but it would rather be expensive to use imi-
dazolide or active ester in an industrial setting.
Recently, Tanabe and coworkers [11] reported an effi-
cient Ti-crossed Claisen esters and acid chlorides to pro-
vide a variety of b-keto esters; this method also suffers
by the usage of imidazoles and costlier TiCl4. Hence,
we indent to improve the efficiency of traditional cross-
Claisen condensation by changing the equivalence of
base, acid chloride, reaction time, sequence of addition
of reactants, temperature, and solvents choosing com-
pound 1 as representative example. The results of every
C
V
2010 HeteroCorporation

324
R. Venkat Ragavan and V. Vijayakumar
Vol 48
Scheme 2
Table 1
Yield of the reaction optimized with different equivalent of reactants.
Cross condensed
product (%)a
Self-condensed
product (%)a
Method
A
B
C
D
E
F
05
13
10
23
47
64
81
68
54
35
22
09
spectroscopy (LC-MS)] in step 1, and the overall yield
of the condensation of b-keto esters with hydrazine
hydrate also observed as moderate (ꢀ 60%). Finally, in
method F, we could achieve the maximum yield.
a Isolated yield.
The above experiments clearly revealed that the usage
of more than 3 equiv. of base avoided the self-condensa-
tion. The highly active oxyacetic acid ethyl ester under-
goes self-Claisen condensation quickly than the other
bulky, sterically hindered esters such as t-butyl, benzyl,
and iso-propyl in the solution phase (solvated) [12], and
hence to avoid the self-condensation, the time lag
should be avoided between the addition of base and acid
chloride (not more than 2 min). Hence, the attention to-
ward rapid addition of base and acid chloride was
indeed. Various new derivatives of pyrazolones from
b-keto ester intermediates were synthesized to test the
generality of this method and their results are given in
Table 4. It revealed that yields were generally good,
although conditions are not optimized for each of the
reactions.
change accomplished have been represented as different
methods A–I (detailed procedure given in Experimental
Section). The yield of cross- and self-condensed prod-
ucts were given in Table 1.
Our initial attempt to synthesize pyrazolone by
method A resulted in undesirable self-condensed pyrazo-
lone as major product (Scheme 1) and the desired cross-
condensed pyrazolone (Scheme 2) as a minor product
(5%). Then the yield of cross-condensed product was
optimized with reference to the compound 1 by chang-
ing the equivalence of base, acid chloride, time, and
order of addition of reactants (methods A–F), and the
results were given in Table 1. After finding the suitable
composition of equivalence of base, acid chloride, and
the order of additions (method F), the reaction condition
was optimized by carrying out the experiment at differ-
ent temperatures (Table 2) and then with different bases
and solvents (Table 3).
In few cases, the hydrazides of corresponding acetic
acid ethyl esters were observed in crude LCMS. Many
functional groups were tolerated with less or no side
products. Mainly, electrophile-containing enolizable
a-protons were successfully coupled with the ester eno-
lates to form b-keto esters. Particularly, cyano function-
ality was retained in compound 5. Steric effect could be
observed in case of compound 8, pyrazolone formation
was affected sterically by the presence of tetrazole ring
(b-keto ester and the corresponding hydrazide was
observed in LCMS). Among the substituted hydrazines,
highly nucleophilic methyl hydrazine worked well under
these conditions and phenyl hydrazine did not react with
b-keto esters in the same conditions due to its less
nucleophilicity. However, the conditions of less
As expected, the yield of self-condensed product was
increased with increasing the temperature. The results
shown in Table 3 clearly revealed that the lithium eno-
late was reacting smoothly with stronger electrophilic
acid chloride compared with other enolates (sodium and
potassium). The reaction between lithium enolate and
the acid chloride was favored in toluene than in tetra-
hyrofuran (THF). The side reactions were slowed down
in a hydrocarbon solvent like toluene which disfavored
the possible formation of the intermediates with charges
and hence the ester enolate react with the acid chloride.
The attempt to improve the yield by carrying out the
experiment in two steps was failed, as we could not iso-
late the b-keto esters as very pure [only 70–80% of pu-
rity was recorded using liquid chromatography-mass
Table 2
Yield of the reaction optimized at different temperatures.
Cross-condensed Self-condensed
product (%)a
Scheme 1
Method Temperature (ꢁC)
product (%)a
G
H
I
ꢂ50
ꢂ20
0
62
57
48
13
15
21
a Isolated yield.
Journal of Heterocyclic Chemistry
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March 2011
A Novel Route to 4-Oxy/thio Substituted-1H-pyrazol-5(4H)-ones via
Efficient Cross-Claisen Condensation
325
Table 3
nucleophilic phenyl hydrazines with the b-keto esters
were successful when we do the reaction in two steps
(see general procedure, method J).
Effect of solvent and base on the yield.
Base
Solvent
Yield (%)a
In summary, an efficient, extremely rapid method that
is hitherto unreported to synthesize a-oxy/thio substi-
tuted b-keto esters from oxy/thio substituted acetic acid
esters and acid chlorides through efficient cross-Claisen
condensation has been developed. The b-keto esters
were treated with hydrazine in situ to get new deriva-
tives of 4-oxy/thio substituted pyrazolones in good yield.
As this method is successful with different oxy/thio ace-
tic acid ethyl esters and acid chlorides, it can be
LiHMDS (1.0M THF)
NaHMDS (1.0M THF)
KHMDS (1.0M THF)
LDA (1.0M THF)
NaOMe
Toluene
Toluene
Toluene
Toluene
THF
64
47
38
31
14
07
38
KOtBu
THF
THF
LiHMDS (1.0M THF)
a Isolated yield.
Table 4
List of 4-oxy/thio substituted-1H-pyrazol-5(4H)-ones prepared by method F.
Product
X
R1
R2
R3
Yield (%)a
1
2
3
4
5
6
7
8
9
O
O
O
O
O
S
APh
ACH3
ACH2A3BrAPh
A4OCH3APh
A4CNAPh
APh
ACH3
A4ClAPh
ACH2CH3
ACH2CH3
ACH3
AH
AH
AH
AH
AH
AH
AH
AH
AH
64
57
60
57
48
74
54
0b
A(CH2)4CH3
ACylopropyl
A2ATetrazolo5Aclorophenyl
APh
S
O
O
ACH2Ph
APh
A4ClAPh
52
10
S
APh
AH
51
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
O
O
O
O
S
APh
APh
ACH2A3BrAPh
A4OCH3APh
APh
ACH2CH3
ACH2OCH3
ACH3
ACH3
ACH3
AIsobutyl
ACH (CH3)2
ACH2CH3
ACH2OCH3
AIsobutyl
A4ClAPh
ACH (CH3)3
AIsobutyl
ACH3
ACH3
ACH3
ACH2CH3
AIsobutyl
ACH3
ACH2CH3
ACH3
AH
AH
AH
AH
AH
AH
AH
AH
AH
57
54
58
62
67
74
S
APh
APh
ACH2Ph
ACH2Ph
A4ClAPh
APh
APh
APh
APh
APh
APh
APh
APh
APh
APh
APh
APh
APh
S
71
61
58
78
59
58
64
0c
0c
S
S
S
AH
AH
AH
ACH3
APh
A4FAPh
ACH3
ACH3
A4FAPh
A4FAPh
ACH2CF3
A4FAPh
A4FAPh
A4FAPh
O
O
O
O
O
S
60
O
O
S
O
O
S
77c
52d
58d
49d
60d
51d
61d
AIsobutyl
ACH2CH3
O
34
35
S
S
APh
APh
A (CH2)4CH3
ACH2CH3
29c,d
40c,d
A4FAPh
a Isolated yield.
b Only b-keto ester and the corresponding hydrazide was observed in crude LCMS.
c Percentage of product in crude LCMS.
d Prepared by method J.
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R. Venkat Ragavan and V. Vijayakumar
Vol 48
method A. Yield of the product was 144 mg (13%). Yield of
the unwanted self-condensed product was 1.12 g (72%).
Method C. Phenoxy acetic acid ethyl ester (1 g, 5.5 mmol)
in toluene was added slowly to the solution of LiHMDS (5.5
mL, 1.0M in THF, 5.5 mmol) in toluene (10 mL) at ꢂ78ꢁC
over a period of 10 min and the mixture stirred at this temper-
ature for 30 min, then acetyl chloride (0.39 mL, 5.5 mmol)
was added slowly to reaction mixture over a period of 5 min
at the same temperature. The resulting solution was slowly (10
min) warmed to ꢂ20ꢁC, then quenched with AcOH (2 mL)
and EtOH (15 mL). Hydrazine hydrate (1.5 mL, 44 mmol)
was added and refluxed for 10 min. The resulting light brown
solution was concentrated to dryness and redissolved in
EtOAc, the separated organic layer was washed with brine so-
lution, dried over Na2SO4, and evaporated under reduced pres-
sure. Crude product was purified by column chromatography
using MeOH:EtOAc (1:99). Yield of the product was 105 mg
(10%). Yield of the unwanted self-condensed product was 1.06
g (68%).
Method D. LiHMDS (5.5 mL, 1.0M in THF, 5.5 mmol)
was added quickly to the solution of phenoxy acetic acid ethyl
ester (1 g, 5.5 mmol) in toluene (15 mL) using syringe at
ꢂ78ꢁC with stirring, and the formed anion is allowed to stand
for ꢀ1 min, then acetyl chloride (0.39 mL, 5.5 mmol) was
added in a lot with stirring. Reaction mixture was removed
from acetone-dry ice bath, stirred for 10 min, and then added
2 mL of AcOH with stirring. EtOH (15 mL) and hydrazine
hydrate (1.5 mL, 44 mmol) were added and refluxed for 10
min. Reaction mixture was concentrated to dryness under
reduced pressure and redissolved in EtOAC, the organic layer
washed with brine solution, dried over Na2SO4, and evaporated
under reduced pressure. Crude product was purified by column
chromatography using MeOH:EtOAc (1:99). Yield of the prod-
uct was 242 mg (23%). Yield of the unwanted self-condensed
product was 548 mg (35%).
Method E. LiHMDS (11.1 mL, 1.0M in THF, 11.1 mmol)
was added quickly using syringe to the solution of phenoxy
acetic acid ethyl ester (1 g, 5.5 mmol) in toluene (15 mL) at
ꢂ78ꢁC with stirring, and the formed anion is allowed to stand
for ꢀ 1 min, then acetyl chloride (0.8 mL, 11.1 mmol) added
in a lot with stirring. Reaction mixture was removed from ace-
tone-dry ice bath and stirred for 10 min, then 2 mL of AcOH
was added with stirring. EtOH (15 mL) and hydrazine hydrate
(1.5 mL, 44 mmol) were added and refluxed for 10 min. Reac-
tion mixture was concentrated to dryness under reduced pres-
sure and redissolved in EtOAc, then organic layer washed with
brine solution, dried over Na2SO4, and evaporated under
reduced pressure. Crude product was purified by column chro-
matography using MeOH:EtOAc (1:99). Yield of the product
was 496 mg (47%). Yield of the unwanted self-condensed
product was 344 mg (22%).
regarded as useful method for the synthesis of previ-
ously inaccessible pyrazolones as well as pharmaceuti-
cally demanding pyrazolones. At present, we are adopt-
ing this method to synthesize other heterocycles, which
originate from b-keto esters.
EXPERIMENTAL
All the reagents were purchased from Aldrich and used as
received. Lithium hexamethyl disilylamide (LiHMDS) solu-
tions were kept under nitrogen atmosphere after opening. Acid
chlorides were freshly prepared and used. Dry toluene, AcOH,
and EtOH were supplied by Spectrochem. All chemistry was
performed under a nitrogen atmosphere using standard techni-
ques. Melting points were determined by Buchi B-545 appara-
tus. All the NMR spectra were recorded using Bruker AMX
400 or Bruker DPX 300 Instrument with 5-mm PABBO BB-
1
1H tubes. H-NMR spectra recorded using ꢀ 0.03M solutions
in d6-DMSO at 300 or 400 MHz with tetramethyl silane
(TMS) as internal reference. 13C-NMR spectra were recorded
using ꢀ 0.05M solutions in d6-DMSO at 75 or 100 MHz with
TMS as internal reference. In many cases, pyrazolones were
recorded in the enol form whenever d6-DMSO was used as
solvent. IR spectra were recorded using NICOLET 6700 FTIR
(Thermo scientific). MALDI experiment was carried out using
laser beam (intensity, 350 nm) in Bruker autoflex III smart
beam. LCMS were obtained using Agilent 1200 series LC and
Micromass zQ spectrometer. Column chromatography was per-
formed using a silica gel (230–400 mesh).
General procedure to synthesis pyrazolones (method
F). LiHMDS (19.4 mL, 1.0M in THF, 19.4 mmol) was added
quickly to the solution of phenoxyacetic acid ethyl ester (1 g,
5.5 mmol) in toluene (15 mL) using syringe at ꢂ78ꢁC with agi-
tation and the formed anion is allowed to stand for ꢀ 2 min.
Then, acetyl chloride (1 mL, 13.8 mmol) was added in a lot
with stirring. The reaction mixture was removed from acetone-
dry ice bath and stirred for 10 min, then 2 mL of AcOH was
added with stirring. EtOH (15 mL) and hydrazine hydrate (1.5
mL, 44 mmol) were added to the reaction mixture, refluxed for
10 min. Then, the reaction mixture was concentrated to dryness
under reduced pressure and redissolved in EtOAc, the organic
layer was washed with saturated brine solution, dried over
Na2SO4, and evaporated under reduced pressure. Crude product
was purified by column chromatography using MeOH:EtOAc
(1:99). Yield of the product was 676 mg (64%). Yield of the
unwanted self-condensed product was 140 mg (9%).
Method A. LiHMDS (5.5 mL, 1.0M in THF, 5.5 mmol) was
added slowly to the solution of phenoxy acetic acid ethyl ester
(1 g, 5.5 mmol) in toluene (15 mL) at ꢂ78ꢁC with stirring (30
min), followed by acetyl chloride (0.39 mL, 5.5 mmol) in drop-
wise at the same temperature. Resulting solution was slowly (10
min) warmed to ꢂ20ꢁC, then quenched with AcOH (2 mL) and
EtOH (15 mL). Hydrazine hydrate (1.5 mL, 4.4 mmol) was
added and refluxed for 10 min. The resulting light brown solu-
tion was concentrated directly and the obtained residue was
redissolved in EtOAc, washed with brine solution, dried over
Na2SO4, and evaporated under reduced pressure. Crude product
was purified by column chromatography using MeOH:EtOAc
(1:99). Yield of the product was 90 mg (8%). Yield of the
unwanted self-condensed product was 1.26 g (81%).
In methods G, H, and I, the reaction was carried out at ꢂ50,
ꢂ20, and 0ꢁC, respectively. The additions and other conditions
were followed as such given in method F.
General procedure to synthesize N-substituted pyrazo-
lones: (Method J). LiHMDS (19.4 mmol, 1M solution in
THF) was added quickly using syringe to the solution of an
ester (5.5 mmol) in toluene (15 mL) at ꢂ30ꢁC with stirring,
the formed anion is allowed to stand for ꢀ 2 min, then acid
chloride (13.8 mmol) was added in one portion with stirring.
Reaction mixture was removed from acetone-dry ice bath and
continues the stirring for 10 min, then quenched with water,
Method B. The LiHMDS in THF was taken as 11.1 mmol
and other additions, conditions were followed as such in
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
A Novel Route to 4-Oxy/thio Substituted-1H-pyrazol-5(4H)-ones via
Efficient Cross-Claisen Condensation
327
and extracted with EtOAc (2 ꢃ 100 mL). Then, combined or-
ganic layer was dried over Na2SO4, concentrated at rotary
evaporator. The obtained crude product was taken in the
mixture of EtOH (20 mL) and AcOH (2 mL), to this substituted
hydrazine (10 mmol) was added and refluxed overnight.
Reaction was monitored by thin layer chromatography (TLC);
reaction mixture was concentrated to dryness. See specific com-
pounds for purification details.
C11H9N3O2: C, 61.39; H, 4.22; N, 19.53. Found: C, 61.44; H,
4.35; N, 19.64.
3-Pentyl-4-(phenylthio)-1H-pyrazol-5(4H)-one (6) This com-
pound was obtained according to above general procedure of
method F. Purified by column chromatography (MeOH:EtOAc,
1:99), white solid. m.p. 182.1–183.5ꢁC; IR (KBr) m 3061,
2953, 2923, 2854, 1587 cmꢂ1 1H-NMR (300 MHz, DMSO-
;
d6): d 12.00 (brs, 1H), 10.00 (brs, 1H), 7.21 (t, J ¼ 7.7 Hz,
2H), 7.05 (t, J ¼ 7.3 Hz, 1H), 6.97 (d, J ¼ 7.3 Hz, 2H),
2.48 (t, J ¼ 7.7 Hz, 2H), 1.46 (m, 2H), 1.21 (m, 4H), 1.13 (t,
J ¼ 5.0 Hz, 3H); 13C-NMR (100 MHz, DMSO-d6): d 162.8,
149.0, 139.8, 129.2, 125.3, 125.0, 87.0, 31.1, 28.2, 25.0, 22.1,
14.2. LC-MS: m/z 263.0 (Mþ); Anal. Calcd. for C14H18N2OS:
C, 64.09; H, 6.91; N, 10.68. Found: C, 64.00; H, 6.98; N,
10.55.
3-Methyl-4-phenoxy-1H-pyrazol-5(4H)-one (1) This com-
pound was obtained according to above general procedure of
method F. Purified by column chromatography (MeOH:EtOAc,
1:99), white solid. m.p. 221.7–222.8ꢁC; IR (KBr): m 3738,
2571, 2296, 1588 cmꢂ1 1H-NMR (400 MHz, DMSO-d6): d
;
9.12 (brs, 1H), 7.27 (t, J ¼ 7.4 Hz, 2H), 6.96 (t, J ¼ 7.3 Hz,
1H), 6.85 (d, J ¼ 7.8 Hz, 2H), 1.96 (s, 3H), 1.36 (brs, 1H);
13C-NMR (100 MHz, DMSO-d6): d 159.1, 152.9, 130.8, 129.3,
121.9, 120.5, 115.1, 9.27; LC-MS: m/z 190.3 (Mþ); Anal.
Calcd. for C10H10N2O2: C, 63.15; H, 5.30; N, 14.73. Found:
C, 63.02; H, 5.18; N, 14.63.
3-Cyclopropyl-4-(phenylmethylthio)-1H-pyrazol-5(4H)-one
(7) This compound was obtained according to above general
procedure of method F. Purified by column chromatography
(MeOH:EtOAc, 1:99), pale yellow solid. m.p. 231.0–231.9ꢁC;
3-(4-Chlorophenyl)-4-methoxy-1H-pyrazol-5(4H)-one (2) This
compound was obtained according to above general procedure
of method F. Purified by preparative high performance liquid
chromatography (HPLC) [MeCN: trifluoro acetic acid (TFA)],
pale brown solid. m.p. 147.8–148.9ꢁC; IR (KBr): m 3292,
IR (KBr) m 3066, 2955, 2923, 2868, 1583 cmꢂ1 1H-NMR
;
(400 MHz, DMSO-d6): d 11.20 (brs, 1H), 9.77 (brs, 1H),
7.24–7.17 (m, 3H), 7.11 (d, J ¼ 6.7 Hz, 2H), 3.69 (s, 2H),
1.58–1.51 (m, 1H), 0.66 (t, J ¼ 2.2 Hz, 2H), 0.58 (t, J ¼ 5.0
Hz, 2H); 13C-NMR (100 MHz, DMSO-d6): d 162.4, 149.3,
139.0, 129.3, 128.5, 127.0, 90.5, 7.2, 7.1; LC-MS: m/z 246.9
(Mþ); Anal. Calcd. for C13H14N2OS: C, 63.39; H, 5.73; N,
11.37. Found: C, 63.53; H, 5.65; N, 11.49.
2944, 2360, 1736, 1656 cmꢂ1 1H-NMR (400 MHz, DMSO-
;
d6): d 8.90 (brs, 2H), 7.73 (d, J ¼ 6.8 Hz, 2H), 7.49 (d, J ¼
7.0 Hz, 2H), 3.70 (s, 3H); 13C-NMR (100 MHz, DMSO-d6): d
152.7, 131.1, 129.5, 128.8, 128.3, 126.7, 126.2, 60.4; LC-MS:
m/z 224.8 (Mþ); Anal. Calcd. for C10H9ClN2O2: C, 53.47; H,
4.04; N, 12.47. Found: C, 53.55; H, 4.24; N, 12.50.
4-(4-Chlorophenoxy)-3-phenyl-1H-pyrazol-5(4H)-one (9) This
compound was obtained according to above general procedure
of method F. Purified by column chromatography (MeOH:E-
tOAc, 1:99), pale yellow solid. m.p. 226.7–227.8ꢁC; IR (KBr)
3-Ethyl-4-(3-bromophenylmethoxy)-1H-pyrazol-5(4H)-one
(3) This compound was obtained according to above general
procedure of method F. Purified by column chromatography
(MeOH:EtOAc, 1:99), pale yellow solid. m.p. 220.1–221.7ꢁC;
m 3447, 3203, 2281, 1614, 1525 cmꢂ1 1H-NMR (400 MHz,
;
CD3OD): d 7.66 (m, 2H), 7.40–7.38 (m, 3H), 7.22 (d, J ¼ 8.6
Hz, 2H), 7.05 (d, J ¼ 8.6 Hz, 2H); 13C-NMR (100 MHz,
DMSO-d6): d 164.6, 149.2, 139.3, 133.4, 131.7, 130.8, 129.9,
128.8, 128.5, 127.8, 88.7; LC-MS: m/z 300.9 (Mþ); Anal.
Calcd. for C15H11ClN2O2: C, 62.80; H, 3.87; N, 9.77. Found:
C, 62.85; H, 3.69; N, 9.77.
IR (KBr): m 2969, 2927, 2722, 2130, 1783, 1715 cmꢂ1 1H-
;
NMR (400 MHz, DMSO-d6): d 10.90 (brs, 1H), 9.70 (brs,
1H), 7.56 (s, 1H), 7.49 (d, J ¼ 6.7 Hz, 1H), 7.36 (t, J ¼ 7.3
Hz, 1H), 7.30 (d, J ¼ 7.5 Hz, 1H); 13C-NMR (100 MHz,
DMSO-d6): d 152.8, 141.1, 135.0, 131.0, 130.9, 130.8, 127.4,
124.3, 121.9, 73.9, 17.2, 13.3; LC-MS: m/z 297.1 (Mþ), Anal.
Calcd. for C12H13BrN2O2: C, 48.50; H, 4.41; N, 9.43. Found:
C, 48.62; H, 4.32; N, 9.39.
3-(6-Chloropyridine-2-yl)-4-(phenylthio)-1H-pyrazol-5 (4H)-
one (10) This compound was obtained according to above gen-
eral procedure of method F. Purified by column chromatogra-
1
phy (MeOH:EtOAc, 1:99), off white semisolid. H-NMR (400
3-Ethyl-4-(4-methoxyphenyoxy)-1H-pyrazol-5(4H)-one (4) This
compound was obtained according to above general procedure of
method F. Purified by column chromatography (MeOH:EtOAc,
1:99), white solid, m.p. 256.3–257.5ꢁC; IR (KBr): m 2937, 2833,
MHz, DMSO-d6): d 13.00 (brs, 1H), 10.50 (brs, 1H), 8.70 (s,
1H), 8.28 (d, J ¼ 8.4 Hz, 1H), 7.67 (d, J ¼ 7.6 Hz, 1H), 7.27
(t, J ¼ 8.0 Hz, 2H), 7.11 (t, J ¼ 7.2 Hz, 1H), 7.04 (d, J ¼ 7.6
Hz, 2H); LC-MS: m/z 303.0 (Mþ).
2702, 1621, 1536 cmꢂ1 1H-NMR (400 MHz, DMSO-d6): d
;
3-Ethyl-4-phenoxy-1H-pyrazol-5(4H)-one (11) This com-
pound was obtained according to above general procedure of
method F. Purified by column chromatography (acetone:E-
tOAc, 1:4), white solid. m.p. 196.2–197.3ꢁC; IR (KBr): m
11.30 (brs, 1H), 9.70 (brs, 1H), 6.83 (d, J ¼ 9.1 Hz, 2H), 6.78
(d, J ¼ 9.3 Hz, 2H), 3.68 (s, 3H), 2.35 (q, J ¼ 7.6 Hz, 2H),
1.03 (t, J ¼ 7.6 Hz, 3H); 13C-NMR (100 MHz, DMSO-d6): d
154.3, 153.3, 153.0, 136.1, 120.6, 115.9, 114.9, 55.8, 17.4, 13.0;
LC-MS: m/z 234.9 (Mþ); Anal. Calcd. for C12H14N2O3: C,
61.53; H, 6.02; N, 11.96. Found: C, 61.38; H, 5.94; N, 12.09.
3-Methyl-4-(4-cyanophenyoxy)-1H-pyrazol-5(4H)-one (5) This
compound was obtained according to above general procedure
of method F. Purified by column chromatography (MeOH:E-
tOAc, 1:99), pale yellow solid. m.p. 281.3–282.8ꢁC; IR (KBr);
3787, 2977, 2698, 1620 cmꢂ1 1H-NMR (400 MHz, DMSO-
;
d6): d 11.30 (s, 1H), 9.70 (s, 1H), 7.27 (t, J ¼ 7.6 Hz, 2H),
6.96 (t, J ¼ 7.4 Hz, 1H), 6.84 (d, J ¼ 7.9 Hz, 2H), 2.35 (q, J
¼ 7.6 Hz, 2H), 1.03 (t, J ¼ 7.6 Hz, 3H); 13C-NMR (75 MHz,
DMSO-d6): d 159.3, 152.9, 136.2, 130.2, 121.8, 119.9, 115.1,
17.4, 13.0; LC-MS: m/z 204.3 (Mþ); Anal. Calcd. for
C11H12N2O2: C, 64.09; H, 5.92; N, 13.72. Found: C, 64.17; H,
5.88; N, 13.64.
1
m 2677, 2221, 1596, 1497 cmꢂ1; H-NMR (400 MHz, DMSO-
3-Methoxymethyl-4-phenoxy-1H-pyrazol-5(4H)-one (12) This
compound was obtained according to above general procedure
of method F. Purified by column chromatography (MeOH:E-
tOAc, 1:99), pale yellow solid. m.p. 146.4–147.2ꢁC; IR (KBr):
d6): d 11.50 (brs, 1H), 9.80 (brs, 1H), 7.76 (d, J ¼ 4.8 Hz,
2H), 7.01 (d, J ¼ 9.6 Hz, 2H), 1.97 (s, 3H); 13C-NMR (75
MHz, DMSO-d6): d 162.5, 152.4, 134.7, 134.6, 119.3, 116.8,
116.3, 104.4, 9.21; LC-MS: m/z 215.9 (Mþ); Anal. Calcd. for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

328
R. Venkat Ragavan and V. Vijayakumar
Vol 48
m 3206, 2930, 2550, 2361, 1587 cmꢂ1
;
1H-NMR (400 MHz,
C12H14N2OS: C, 61.51; H; 6.02; N, 11.96. Found: C, 61.44;
H; 5.98; N, 12.06.
DMSO-d6): d 11.70 (s, 1H), 9.80 (s, 1H), 7.27 (t, J ¼ 7.4 Hz,
2H), 6.97 (t, J ¼ 7.3 Hz, 1H), 6.87 (d, J ¼ 8.6 Hz, 2H), 4.16
(s, 2H), 3.15 (s, 3H); 13C-NMR (75 MHz, DMSO-d6): d 159.1,
152.3, 131.3, 129.7, 122.0, 121.3, 115.2, 62.8, 57.76; LC-MS:
m/z 220.1 (Mþ); Anal. Calcd. for C11H12N2O3: C, 59.99; H,
5.49; N, 12.72. Found: C, 60.08; H, 5.319; N, 12.68.
3-Ethyl-4-(benzylthio)-1H-pyrazol-5(4H)-one (18) This com-
pound was obtained according to above general procedure of
method F. Purified by column chromatography (MeOH:EtOAc,
1:9), white solid. m.p. 226.9–227.8ꢁC; IR (KBr): m 3061,
3024, 2930, 1576 cmꢂ1 1H-NMR (400 MHz, DMSO-d6): d
;
3-Methyl-4-(3-bromophenylmethoxy)-1H-pyrazol-5(4H)-one
(13) This compound was obtained according to above general
procedure of method F. Purified by column chromatography
(MeOH:EtOAc, 1:99), white solid. m.p. 183.6–184.7ꢁC; IR
11.50 (brs, 1H), 9.80 (brs, 1H), 7.25–7.08 (m, 3H), 7.07 (d, J
¼ 6.6 Hz, 2H), 3.66 (s, 2H), 2.10 (q, J ¼ 8.0 Hz, 2H), 0.84 (t,
J ¼ 7.6 Hz, 3H); 13C-NMR (100 MHz, DMSO-d6): d 162.5,
149.4, 139.1, 129.2, 128.4, 126.9, 89.4, 18.1, 13.3; LC-MS: m/
z 234.9 (Mþ); Anal. Calcd. for C12H14N2OS: C, 61.51; H,
6.02; N, 11.96. Found: C, 61.50; H, 6.06; N, 11.88.
1
(KBr): m 2966, 2923, 2871, 2557, 2361, 1588 cmꢂ1; H-NMR
(400 MHz, DMSO-d6): d 10.80 (brs, 1H), 9.60 (brs, 1H), 7.57
(s, 1H), 7.50 (d, J ¼ 5.9 Hz, 1H), 7.37 (d, J ¼ 5.8 Hz, 1H),
7.31 (t, J ¼ 7.7 Hz, 1H), 4.81 (s, 2H), 1.90 (s, 3H); 13C-NMR
(75 MHz. DMSO-d6): d 152.8, 141.2, 131.0, 130.9, 130.85,
129.4, 127.4, 125.12, 121.9, 73.9, 9.2; LC-MS: m/z 283.8
(Mþ); Anal. Calcd. for C11H11BrN2O2: C, 46.66; H, 3.92; N,
9.89. Found: C, 46.54; H, 3.84; N, 9.82.
3-Methoxymetyl-4-(benzylthio)-1H-pyrazol-5(4H)-one (19) This
compound was obtained according to above general procedure
of method F. Purified by column chromatography (Pet. ether:-
EtOAc, 1:1), white solid. m.p. 226.6–227.9ꢁC; IR (KBr): m
3058, 2982, 2817, 2362, 1577 cmꢂ1 1H-NMR (400 MHz,
;
DMSO-d6): d 7.31–7.17 (m, 3H), 7.07 (d, J ¼ 7.6 Hz, 2H),
3.79 (s, 2H), 3.69 (s, 2H), 3.13 (s, 3H); 13C-NMR (100 MHz,
CD3OD): d 164.3, 148.3, 140.7, 130.7, 129.7, 128.3, 93.1,
65.7, 59.0, 41.3; LC-MS: m/z 251.0 (Mþ); Anal. Calcd. for
C12H14N2O2S: C, 57.51; H, 5.68; N, 11.04. Found: C, 57.51;
H, 5.68; N, 11.04.
3-Methyl-4-(4-methoxyphenyoxy)-1H-pyrazol-5(4H)-one (14) This
compound was obtained according to above general procedure
of method F. Purified by column chromatography (MeOH:E-
tOAc, 1:99), white solid. m.p. 201.0–202.7ꢁC; IR (KBr): m
2833, 2701, 1621, 1572 cmꢂ1 1H-NMR (300 MHz, DMSO-
;
d6): d 11.20 (brs, 1H), 9.70 (brs, 1H), 6.25 (d, J ¼ 7.2 Hz,
2H), 6.80 (d, J ¼ 6.7 Hz, 2H), 3.67 (s, 3H), 1.90 (s, 3H); 13C-
NMR (75 MHz, DMSO-d6): d 154.4, 153.1, 152.9, 130.7,
121.4, 116.0, 114.9, 55.8, 9.26; LC-MS: m/z 220.9 (Mþ);
Anal. Calcd. for C11H12N2O3: C, 59.99; H, 5.49; N, 12.72.
Found: C, 60.07; H, 5.55; N, 12.68.
3-Methyl-4-phenylthio-1H-pyrazol-5(4H)-one (15) This com-
pound was obtained according to above general procedure of
method F. Purified by column chromatography (MeOH:EtOAc,
1:99), pale yellow solid. m.p. 292.3–294.1ꢁC; IR (KBr): m 3007,
2656, 1575, 1478 cmꢂ1; 1H-NMR (300 MHz, DMSO-d6): d 10.00
(brs, 1H), 7.22 (t, J ¼ 7.7 Hz, 2H), 7.06 (t, J ¼ 7.5 Hz, 1H), 6.96
(d, J ¼ 8.3 Hz, 2H), 2.08 (s, 3H); 13C-NMR (100 MHz, DMSO-
d6): d 162.7, 145.0, 139.5, 129.3, 125.2, 125.1, 87.3, 10.7; LC-MS:
m/z 206.9 (Mþ); Anal. Calcd. for C10H10N2OS: C, 58.23; H, 4.89;
N, 13.58. Found: C, 58.18; H, 4.76; N, 13.45.
3-Isobutyl-4-(4-chlorophenylthio)-1H-pyrazol-5(4H)-one (20) This
compound was obtained according to above general procedure
of method F. Purified by column chromatography (Pet. ether:-
EtOAc, 1:1), off white solid. m.p. 227–228ꢁC; IR (KBr): m
2956, 2869, 1701, 1603 cmꢂ1 1H-NMR (400 MHz, DMSO-
;
d6): d 12.00 (brs, 1H), 10.00 (brs, 1H), 7.29 (d, J ¼ 8.4 Hz,
2H), 6.98 (d, J ¼ 6.8 Hz, 2H), 2.36 (d, J ¼ 6.8 Hz, 2H), 1.85
(m, 1H), 0.78 (d, J ¼ 6.4 Hz, 6H); 13C-NMR (100 MHz,
DMSO-d6) d 162.7, 147.9, 138.9, 129.5, 129.1, 126.8, 87.1,
34.2, 28.2, 22.6; LC-MS: m/z 282.6 (Mþ); Anal. Calcd. for
C13H15ClN2OS: C, 55.21; H, 5.35; N, 9.91. Found: C, 55.11;
H, 5.24; N, 9.84.
3-(4-Chlorophenyl)-4-phenoxy-1H-pyrazol-5(4H)-one (21) This
compound was obtained according to above general procedure
of method F. Purified by column chromatography (MeOH:E-
tOAc, 1:99), pale yellow solid. m.p. 208.2–209.9ꢁC; IR (KBr):
m 3915, 3787, 3661, 2740, 1589 cmꢂ1 1H-NMR (300 MHz,
;
3-Isobutyl-4-(phenylthio)-1H-pyrazol-5(4H)-one (16) This
compound was obtained according to above general procedure
of method F. Purified by column chromatography (Pet. ether:-
EtOAc, 1:1), pale yellow solid. m.p. 198.1–198.4ꢁC; IR (KBr)
DMSO-d6): d 12.20 (brs, 1H), 10.10 (brs, 1H), 7.63 (d, J ¼
8.3 Hz, 2H), 7.45 (d, J ¼ 10.7 Hz, 2H), 7.28 (t, J ¼ 8.0 Hz,
2H), 6.98 (t, J ¼ 7.5 Hz, 1H), 6.91 (d, J ¼ 7.7 Hz, 2H); 13C-
NMR (75 MHz, DMSO-d6): d 158.3, 132.8, 130.1, 129.4,
126.8, 122.4; LC-MS: m/z 287.2 (Mþ); Anal. Calcd. for
C15H11ClN2O2: C, 62.84; H, 3.87; N, 9.77. Found: C, 62.87;
H, 3.78; N, 9.66.
3-Tert-butyl-4-phenoxy-1H-pyrazol-5(4H)-one (22) This com-
pound was obtained according to above general procedure of
method F. Purified by preparative HPLC, brown semisolid. IR
(KBr): m 2964, 2868, 2716, 1599, 1562 cmꢂ1 1H-NMR (300
;
m 3061, 2954, 2866, 2591, 1590 cmꢂ1 1H-NMR (400 MHz,
;
DMSO-d6): d 12.00 (brs, 1H), 10.00 (brs, 1H), 7.22 (t, J ¼ 7.6
Hz, 2H), 7.07 (t, J ¼ 7.2 Hz, 1H), 6.97 (d, J ¼ 7.6 Hz, 2H),
2.36 (d, J ¼ 7.6 Hz, 2H), 1.85 (m, 1H), 0.90 (d, J ¼ 4.4 Hz,
6H); 13C-NMR (100 MHz, DMSO-d6): d 162.8, 147.9, 139.7,
129.1, 125.2, 124.9, 87.5, 34.2, 28.2, 22.6; LC-MS: m/z 248.9
(Mþ); Anal. Calcd. for C13H16N2OS: C, 62.87; H, 6.49; N,
11.28. Found: C, 62.80; H, 6.41; N, 11.20.
MHz, DMSO-d6): d 10.00 (brs, 2H), 7.26 (t, J ¼ 7.4 Hz, 2H),
6.94 (t, J ¼ 7.0 Hz, 1H), 6.83 (d, J ¼ 7.5 Hz, 2H), 1.16 (s,
9H); 13C-NMR (75 MHz, DMSO-d6): d 159.0, 153.1, 142.7,
129.8, 121.8, 119.0, 115.1, 31.7, 29.2; LC-MS: m/z 232.3
(Mþ); Anal. Calcd. for C13H16N2O2: C, 67.22; H, 6.94; N,
12.06. Found: C, 67.09; H, 6.89; N, 12.186.
3-Isobutyl-1-methyl-4-phenoxy-1H-pyrazol-5(4H)-one (23) This
compound was obtained according to above general procedure
of method F. Purified by column chromatography (MeOH:
CH2Cl2, 2:98), pale brown solid. m.p. 141.4–142.7ꢁC; IR
3-Isopropyl-4-(phenylthio)-1H-pyrazol-5(4H)-one (17) This
compound was obtained according to above general procedure
of method F. Purified by column chromatography (Pet. ether:-
EtOAc, 1:1), white solid. m.p. 216.1–217.2ꢁC; IR (KBr): m
3054, 2970, 2735, 1604 cmꢂ1 1H-NMR (400 MHz, DMSO-
;
d6): d 12.00 (brs, 1H), 10.00 (brs, 1H), 7.23 (t, J ¼ 7.6 Hz,
2H), 7.07 (t, J ¼ 7.2 Hz, 1H), 6.97 (d, J ¼ 7.6 Hz, 2H), 2.96
(m, 1H), 1.15 (d, J ¼ 9.6 Hz, 6H); 13C-NMR (100 MHz,
DMSO-d6): d 162.8, 154.0, 139.8, 129.2, 125.1, 125.0, 85.6,
25.8, 21.9; LC-MS: m/z 233.8 (Mþ); Anal. Calcd. for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
A Novel Route to 4-Oxy/thio Substituted-1H-pyrazol-5(4H)-ones via
Efficient Cross-Claisen Condensation
329
(KBr): m 3188, 2956, 2870, 1693, 1588 cmꢂ1
;
1H-NMR (400
¼ 7.5 Hz, 4H), 7.01(t, J ¼ 6.9 Hz, 1H), 6.94 (d, J ¼ 8.3 Hz,
2H), 2.48 (s, 3H); 13C-NMR (100 MHz, DMSO-d6): d 160.7,
158.2, 140.9, 129.6, 129.4, 21.9, 115.8, 115.5, 114.8,
10.9; LC-MS: m/z 284.5 (Mþ); Anal. Calcd. for
C16H13FN2O2: C, 67.60; H, 4.61; N, 9.85. Found: C, 67.55; H,
4.76; N, 9.735.
MHz, CD3OD): d 7.27 (t, J ¼ 7.5 Hz, 2H), 6.97 (t, J ¼ 7.3
Hz, 1H), 6.92 (d, J ¼ 7.6 Hz, 2H), 3.48 (s, 3H), 2.31 (d, J ¼
7.3 Hz, 2H), 1.89 (m, 1H), 0.96 (d, J ¼ 6.3 Hz, 6H); 13C-
NMR (100 MHz, CD3OD): d 160.2, 142.7, 130.8, 123.4,
116.3, 34.9, 32.0, 29.2, 22.0; LC-MS: m/z 247.0 (Mþ); Anal.
Calcd. for C14H18N2O2: C, 68.27; H, 7.37; N, 11.37; O, 12.29.
Found: C, 68.15; H, 7.26; N, 11.297.
1-(4-Fluorophenyl)-3-isobutyl-4-(phenylthio)-1H-pyrazol-5(4H)-
one (32) This compound was obtained according to above gen-
eral procedure of method J. Purified by column chromatogra-
phy (30% EtOAc in Pet. ether), white solid. m.p. 219.4–
1,3-Dimethyl-4-(phenylthio)-1H-pyrazol-5(4H)-one (26) This
compound was obtained according to above general procedure
of method F. Purified by column chromatography
(MeOH:CH2Cl2, 2:98), pale brown solid. m.p. 170.5–171.8ꢁC;
1
220.6ꢁC, IR (KBr): m 3061, 3026, 2652, 1736, 1577 cmꢂ1; H-
NMR (400 MHz, DMSO-d6): d 12.20 (brs, 1H), 7.75 (d, J ¼
8.5 Hz, 2H), 7.28 (m, 4H), 7.08 (m, 3H), 2.35 (d, J ¼ 3.1 Hz,
2H), 1.92 (m, 1H), 0.84 (d, J ¼ 6.6 Hz, 6H); 13C-NMR
IR (KBr): m 3065, 2918, 2359, 1583 cmꢂ1 1H-NMR (400
;
MHz, DMSO-d6): d 11.30 (brs, 1H), 7.25 (t, J ¼ 8.0 Hz, 3H),
7.09 (t, J ¼ 7.2 Hz, 1H), 6.98 (d, J ¼ 7.6 Hz, 1H), 3.15 (brs,
3H), 1.98 (brs, 3H); 13C-NMR (100 MHz, DMSO-d6): d 155.6,
149.8, 139.6, 129.4, 125.1, 125.1, 49.1, 33.9, 12.6; LC-MS: m/
z 220.2 (Mþ); Anal. Calcd. for C11H12N2OS: C, 59.97; H,
5.49; N, 12.72; Found: C, 60.07; H, 5.41; N, 12.68.
(100 MHz, DMSO-d6):
d 161.5, 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; LC-MS: m/z 320.8 (Mþ); Anal. Calcd. for
C19H19FN2OS: C, 66.64; H, 5.59; N, 8.18. Found: C, 66.57;
H, 5.51; N, 8.22.
1-(4-Flurophenyl)-3-isobutyl-4-phenoxy-1H-pyrazol-5(4H)-
one (28) This compound was obtained according to above
general procedure of method J. Purified by column chromatog-
raphy (MeOH:EtOAc, 1:9), white solid. m.p. 198–199.4ꢁC; IR
3-Ethyl-1-(4-fluorophenyl)-4-phenoxy-1H-pyrazol-5(4H)-one
(33) This compound was obtained according to above general
procedure of method J. Purified by column chromatography
(30% EtOAc in Pet. ether), white solid. m.p. 168.3–169.5ꢁC;
(KBr): m 3077, 2954, 2922, 2867, 1590 cmꢂ1
;
1H-NMR (400
IR (KBr): m 3066, 2980, 2880, 2777, 2702, 2627, 1623 cmꢂ1
;
MHz, DMSO-d6): d 7.69 (m, 2H), 7.27 (m, 4H), 7.01 (m, 3H),
2.39 (d, J ¼ 7.1 Hz, 2H), 1.98 (m, 1H), 0.94 (d, J ¼ 6.6 Hz,
6H); 13C-NMR (100 MHz, DMSO-d6): d 158.8, 144.4, 144.1,
135.9, 130.0, 123.0, 122.3, 121.5, 116.0, 115.3, 35.5, 27.5,
22.8; LC-MS: m/z 325.5 (Mþ); Anal. Calcd. for
C19H19FN2O2: C, 69.92; H, 5.87; N, 8.58. Found: C, 69.81; H,
5.82; N, 8.47.
1H-NMR (400 MHz, DMSO-d6): d 11.58 (brs, 1H), 7.75 (d, J
¼ 8.8 Hz, 2H), 7.32 (t, J ¼ 7.2 Hz, 3H), 7.00 (m, 3H), 2.34
(brs, 2H), 1.60 (brs, 3H); 13C-NMR (100 MHz, DMSO-d6): d
158.8, 146.3, 135.9, 130.1, 123.1, 122.3, 119.2, 166.2, 116.0,
115.5, 115.2, 19.8, 12.5; LC-MS: m/z 298.6 (Mþ); Anal.
Calcd. for C17H15FN2O: C, 68.45; H, 5.07; N, 9.39. Found: C,
68.33; H, 5.15; N, 9.21.
1-(4-Flurophenyl)-3-methyl-4-(phenylthio)-1H-pyrazol-5 (4H)-
one (29) This compound was obtained according to above gen-
eral procedure method of J. Purified by column chromatogra-
phy (MeOH:EtOAc, 1:99), pale yellow solid. m.p. 202.1–
Acknowledgments. The authors are grateful to Syngene Interna-
tionl Pvt. Ltd., (Dr. Goutham Das and Dr. P. Sathya Shanker) for
their invaluable support.
202.6ꢁC; IR (KBr): m 3067, 2447, 1583 cmꢂ1 1H-NMR (400
;
MHz, DMSO-d6): d 11.57 (brs, 1H), 7.74 (m, 2H), 7.30 (m,
4H), 7.01 (t, J ¼ 7.2 Hz, 1H), 6.95 (d, J ¼ 8.4 Hz, 2H),
1.98 (brs, 3H); 13C-NMR (100 MHz, DMSO-d6): d 161.5,
159.1, 152.4, 138.8, 135.1, 129.5, 125.4, 123.4, 116.3, 116.4,
12.8; LC-MS: m/z 299.7 (Mþ); Anal. Calcd. for
C16H13FN2OS: C, 63.98; H, 4.36; N, 9.33. Found: C, 64.07;
H, 4.25; N, 9.26.
REFERENCES AND NOTES
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land, 1986; Vol.19, p 355.
3-Ethyl-1-(4-(2,2,2-trifluoroethyl)phenyl)-4-phenoxy-1H-pyra-
zol-5(4H)-one (30) This compound was obtained according to
above general procedure of method J. Purified by column chro-
matography (MeOH:EtOAc, 1:99), white solid. m.p. 189.7–
[3] Barba, O.; Jones, L. H. US Patent 029,042, 2004.
[4] (a) Hiremath, S. P.; Saundane, A. R.; Mruthyunjayaswamy,
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Hopson, C. B.; Huang, Y.; Keenan, R. M.; Lamb, P.; Leong, L.; Liu, N.;
Miller, S. G.; Price, A. T.; Rosen, J.; Shaw, T. N.; Smith, H.; Stark, K.
C.; Tain, S. S.; Tyree, C.; Wiggall, K. J.; Zhang, L.; Luengo, J. I. J Med
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P. M.; Mark, H. S. J Med Chem 1995, 38, 3524; (d) Darin, E. K.; Miller,
R. B.; Mark, J. K. Tetrahedron Lett 1999, 40, 3535; (e) Janja, M.; Vinko,
S. Heterocycles 1995, 41, 1207.
1
190.4ꢁC; IR (KBr): m 2976, 2500, 1583, 1489 cmꢂ1; H-NMR
(400 MHz, DMSO-d6): d 11.37 (brs, 1H), 7.30 (t, J ¼ 8.3 Hz,
3H), 6.99 (t, J ¼ 7.3 Hz, 1H), 6.86 (d, J ¼ 8.0 Hz, 2H), 4.69
(brs, 2H), 2.25 (q, J ¼ 7.4 Hz, 2H), 0.99 (t, J ¼ 7.3 Hz, 3H);
13C-NMR (100 MHz, DMSO-d6): d 158.5, 145.6, 144.4, 129.6,
129.3, 128.0, 125.2, 122.4, 121.8, 119.6, 117.0, 114.9, 114.7,
47.5, 19.2; LC-MS: m/z 285.9 (Mþ); Anal. Calcd. for
C13H13F3N2O2: C, 54.55; H, 4.58; N, 9.79; Found: C, 54.46;
H, 4.51; N, 9.88.
[5] (a) Boeckman, R. K.; Reed, J. E.; Ge, P. Org Lett 2001, 3,
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4315.
1-(4-Flurophenyl)-3-methyl-4-phenoxy-1H-pyrazol-5(4H)-one
(31) This compound was obtained according to above general
procedure of method J. Purified by column chromatography
(MeOH:EtOAc, 1:99), pale yellow solid. m.p. 190.2–191.7ꢁC;
[6] (a) Gillbert, S.; Jeffery, D. W.; Nicholas, A. S. Tetrahedron
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IR (KBr): m 3084, 2922, 2687, 1721, 1632 cmꢂ1
;
1H-NMR
(400 MHz, DMSO-d6): d 7.75 (d, J ¼ 4.5 Hz, 2H), 7.30 (d, J
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

330
R. Venkat Ragavan and V. Vijayakumar
Vol 48
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