Efficient synthesis of 4-ethoxycarbonyl pyrazolin-5-one derivatives

Article abstract of DOI:10.1081/SCC-120015395

Concise and efficient methods for the preparation of 3-substituted 4-ethoxycarbonylpyrazolin-5-ones are described. The synthetic strategies involve carbon-acylation in the presence of base, followed by ring cyclization with hydrazine or hydrazine monohydrochloride.

Full text of DOI:10.1081/SCC-120015395

This article was downloaded by: [Brown University]
On: 19 May 2013, At: 06:27
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
EFFICIENT SYNTHESIS OF 4-ETHOXYCARBONYL
PYRAZOLIN-5-ONE DERIVATIVES
Jae C. Jung a , E. Blake Watkins a & Mitchell A. Avery b
a Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, P.O. Box
1848, University, MS, 38677-1848, U.S.A.
b Department of Chemistry, University of Mississippi, P.O. Box 1848, University, MS,
38677-1848, U.S.A.
Published online: 23 Aug 2006.
To cite this article: Jae C. Jung , E. Blake Watkins & Mitchell A. Avery (2002): EFFICIENT SYNTHESIS OF 4-ETHOXYCARBONYL
PYRAZOLIN-5-ONE DERIVATIVES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 32:24, 3767-3777
To link to this article: http://dx.doi.org/10.1081/SCC-120015395
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to
anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the contents
will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses should
be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims,
proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or indirectly in
connection with or arising out of the use of this material.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
SYNTHETIC COMMUNICATIONS
Vol.32, No.24, pp.3767–3777, 2002
EFFICIENT SYNTHESIS OF
4-ETHOXYCARBONYL
PYRAZOLIN-5-ONE DERIVATIVES
Jae C. Jung,1 E. Blake Watkins,1
and Mitchell A. Avery1,2,3,
*
1Department of Medicinal Chemistry,
School of Pharmacy
3
2Department of Chemistry, and National Center for
Natural Products Research, University of Mississippi,
P.O. Box 1848, University, MS 38677-1848, USA
ABSTRACT
Concise and efficient methods for the preparation of 3-substi-
tuted 4-ethoxycarbonylpyrazolin-5-ones are described.The
synthetic strategies involve carbon-acylation in the presence
of base, followed by ring cyclization with hydrazine or hydra-
zine monohydrochloride.
Key Words: Pyrazolin-5-ones; Cyclocondensation; Acyl Di-
ethylmalonates
Derivatives of pyrazolin-5-one posses important pharmacological
properties including analgesic, antipyretic, and antiinflammatory proper-
ties.[1] They are also useful intermediates for many industrial products,
*Corresponding author.E-mail: mavery@olemisse.du
3767
DOI: 10.1081/SCC-120015395
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3768
JUNG, WATKINS, AND AVERY
e.g., color photography[2] and liquid crystals.[3] Several syntheses of these
compounds, based on 1,3-diketone ring cyclization with hydrazine, have
been reported in the literature.[4–6] Unfortunately, most of these methods
require tedious isolation and give only poor to moderate yields.During our
study on cycloaddition reaction of azo dienophiles, we realized that a more
efficient method of preparing derivatives of pyrazolin-5-ones was needed.
In this paper, we present simple and improved methods for the preparation
of a-acylated diethylamalonates and 4-ethoxy-carbonylpyrazolin-5-ones.
Our synthesis of substituted pyrazolin-5-ones required suitably substi-
tuted acyl malonates.We chose to prepare these acyl malonates from diethyl
malonate and the corresponding acyl chloride by treatment with a suitable
base (Sch.1).To determine the best method for preparing the desired acyl
malonates, the reaction was performed in the presence of various bases.
The bases used included n-BuLi, NaH, NaOEt, Mg(OEt)2, and t-BuOK.
The results are shown in Table 1.
Magnesium ethoxide proved to be the superior base and consistently
gave 10–25% higher yields than the other bases studied, even when sterically
hindered acyl chlorides were used (Table 1, Entry 9).It seems probable
that the effectiveness of magnesium ethoixde can be explained in part by a
magnesium(II) chelation effect.[7]
Having determined the optimum reaction conditions, the remaining
acyl malonates were synthesized in excellent yields (Table 2).This method
proved effective for both short and long chain, as well as aryl, acyl chlorides.
With the acyl malonates in hand, we turned our attention to formation
of the desired pyrazolin-5-ones.Cyclization of a-acylated diethylmalonates
2a–j was achieved by treatment with hydrazine solution (pH 7), hydrazine
monohydrochloride or hydrazine (55%) in acetic acid to give 4-ethoxycarbo-
nyl pyrazolin-5-ones in 80–90% yield with varying substitution in the 3-posi-
tion (Sch.1).The results of the cyclization reactions are shown in Table 3.
Similarly, we found that ethyl 3-amino-2-ethoxycarbonyl-2-butenoate
(4)[8] or ethyl 3-amino-2-phenylaminocarbonyl-2-butyrate (5)[9] underwent
(a) 1) Mg, EtOH, CCl4/toluene, ii) RCOCl; (b) Method A: H2NNH2 (pH ¼ 7),
EtOH/H2O; Method B: H2NNH2HCl/EtOH; Method C: H2NNH2 (55%)/HOAc.
Scheme 1.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
4-ETHOXYCARBONYL PYRAZOLIN-5-ONE DERIVATIVES
3769
Table 1. Acylation of Diethyl Malonate with Acyl Chlorides Using Various Bases
Entry
R
Base/Solvent
Time (h)
Yielda (%)
Product
1
2
3
4
5
n-BuLi/THF
NaOEt/EtOH
NaH/THF
Mg(OEt)2/toluene
t-BuOK/THF
2
3
3
1
3
74
50
66
82
54
Me
t-Bu
Ph
2a
6
7
8
9
10
n-BuLi/THF
NaOEt/EtOH
NaH/THF
Mg(OEt)2/toluene
t-BuOK/THF
2
3
3
1
3
70
61
66
88
65
2c
2g
2h
11
12
13
14
15
n-BuLi/THF
NaOEt/EtOH
NaH/THF
Mg(OEt)2/toluene
t-BuOK/THF
2
3
3
1
3
59
56
71
89
65
16
17
18
19
20
n-BuLi/THF
NaOEt/EtOH
NaH/THF
Mg(OEt)2/toluene
t-BuOK/THF
2
3
3
1
3
52
60
73
86
75
4-MeOC6H4
aIsolated yields.
Table 2. Synthesis of Acyl Malonates from Diethyl Malonate and Acyl Chlorides
Entry
R
Yielda (%)
Product
1
2
3
4
5
6
Et
c-C5H9
(CH2)4CH3
(CH2)8CH3
Bz
88
87
87
89
90
84
2b
2d
2e
2f
2i
CH2-Bz
2j
aIsolated yield.
ring cyclization with hydrazine monohydrochloride or hydrazine (55%) in
acetic acid to give 3-methyl-4-ethoxycarbonylpyrazolin-5-one (3a) in 86%
and 91% yields, respectively (Sch.2).
Cyclization was achieved in all cases where steric hindrance was not
present.In the case of 2c, 2d, 2g, and 2h the bulkiness of the substituents

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3770
JUNG, WATKINS, AND AVERY
Table 3. Cyclization of Acyl Malonates
Yielda
(%)
Entry
R
Method
Product
1
2
3
4
5
6
7
8
9
10
Me
Et
t-Bu
c-C5H9
(CH2)4CH3
(CH2)8CH3
Ph
4-OMe-Ph
Bz
CH2-Bz
A
C
B, C
B, C
B
85 (86)b (91)c
3a
3b
–
81
NRd
NRd
80
–
3c
3d
–
–
3e
3f
C
86
B, C
B, C
C
NRd
NRd
81
B
80
aIsolated pure yield.
bMethod B.
cMethod C.
dNo reaction.
(a) Method A: H2NNH2 (pH ¼ 7), EtOH/H2O; Method B: H2NNH2HCl/EtOH;
Method C: H2NNH2 (55%)/HOAc.
Scheme 2.
prohibited ring closure.Cyclization failed when R was a phenyl group
(Entry 7, Table 3) but was successful when R was a benzyl group (Entry 9,
Table 3).The addition of a methylene undoubtedly allows clearance for the
hydrazine to add and for cyclization to take place.
Unfortunately, when diethyl acetylmalonate (2a) was treated with
hydrazine (98%) in ethanol, a mixture of diethyl malonate (1) and malo-
nyldihydrazide (6), due to b-carbon cleavage, was isolated in 24% and 45%
yields, respectively.Furthermore, the b-enamino carbonyl compounds 4 and
5 were converted to malonanilic acid ethyl ester (7a), malonanilic acid
hydrazide (7b), ethoxycarbonylacetohydrazide (8), and diethyl malonate (1),

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
4-ETHOXYCARBONYL PYRAZOLIN-5-ONE DERIVATIVES
3771
(a) H2NNH2 (80%)/EtOH.
Scheme 3.
as b-carbon cleavage products, upon treatment with hydrazine (80%) in
ethanol (Sch.3).
In conclusion, we report the efficient synthesis of a-acylated diethyl
malonates and 4-ethoxycarbonylpyrazolin-5-ones in high yield.The opera-
tional simplicity, inexpensive and readily available materials make this
procedure a useful alternative to the currently available methods.
EXPERIMENTAL
Reactions requiring anhydrous conditions were performed with the
usual precautions for rigorous exclusion of air and moisture.Tetrahydro-
furan was distilled from sodium bezophenone ketyl prior to use.Thin layer
chromatography (TLC) was performed on precoated silica gel 60 F254
plates from EM reagents and visualized with a 254-nm UV light.Flash
chromatography was carried out on silica gel 60 (E.M. Merck, particle size
1
0.040–0.063 mm, 230–400 mesh ASTM). H NMR and 13C NMR spectra
were recorded on a Bruker DPX 300 at 300 MHz and 76 MHz, respec-
tively.The chemical shifts were reported in parts per million (ppm) down-
field from tetramethylsilane, and J-values were in Hz.IR spectra were
obtained on an ATI Mattson FT/IR spectrometer.Mass spectra were
recorded on a Bruker BioApex FTMS system.All mp. s. were uncorrected.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3772
JUNG, WATKINS, AND AVERY
When necessary, chemicals were purified according to the reported
procedures.[10]
GeneralProcedure for the Preparation of a-Acylated Diethyl
Malonates (2a–f ) with Magnesium Ethoxide
A
mixture of diethyl malonate (1, 10.0 mmol), magnesium
(10.0 mmol), ehtanol (33.0 mmol), CCl4 (0.25 mL) and anhydrous toluene
(22 mL) was stirred under argon at room temperature for 30 min.The
mixture was refluxed for 1 h and then cooled to 0–5ꢀC.The acylating
reagent (10.0 mmol) was added dropwise to the solution at 0–5ꢀC for
30 min, and the reaction mixture was stirred at room temperature for
ꢀ
1 h.The resulting mixture was recooled to 0–5 C and washed with cold
5% aq.HCl solution (20 mL), sat’d NaHCO solution (20 mL) and brine
3
(20 mL).The organic layer was dried over anhydrous MgSO and concen-
4
trated under reduced pressure to give pale yellow liquids.The product was
purified by column chromatography (10% ethyl acetate : hexane) to give a
colorless oil.
GeneralProcedure for the Preparation of a-Acylated Diethyl
Malonates (2a, c, g, h) with Various Bases
To a stirred suspension o diethyl malonate (1, 12.0 mmol) and base
(12.0 mmol) in anhydrous solvents, the acylating agent (12.0 mmol) was
added dropwise at 0–10ꢀC for 30 min.The reaction mixture was stirred
for 1–3 h.After removal of the solvent, the residue was treated with ethyl
acetate (20 mL) and washed with cold 5% aq.HCl solution (20 mL), sat’d
NaHCO3 solution (20 mL) and brine (20 mL).The organic layer was dried
over anhydrous MgSO4 and concentrated to give pale yellow liquids.
Diethylacetyml aol nate (2a): Rf ¼ 0.45 (20% ethyl acetate in hexanes);
1
IR (neat, NaCl) 2984, 1729, 1650, 1469, 1090 cmÀ1; H NMR[11a] (CDCl3)
ꢀ 13.45, 4.38 (br s, br s, total 1H), 4.23–4.13 (m, 4H), 2.27, 2.13 (s, s, total
3H), 1.27–1.19 (m, 6H); 13C NMR (CDCl3) ꢀ 197.04, 171.55, 166.41, 100.19,
62.19, 61.40, 21.01, 14.39, 14.30; MS (ESI) (m/z) 203 [M þ H]þ, 179, 157
(base peak); 225 [M þ Na]þ.
Diethyl propionylmalonate (2b): Rf ¼ 0.55 (20% ethyl acetate in
1
hexanes); IR (neat, NaCl) 3443, 2984, 1734, 1604, 1034 cmÀ1; H NMR[11b]
(CDCl3) ꢀ 13.31, 4.37 (br s, br s, total 1H), 4.17–4.07 (m, 4H), 2.53 (q,
J ¼ 7.13, 1H), 2.35 (q, J ¼ 7.13, 1H), 1.21–1.15 (m, 6H), 1.08 (t, J ¼ 7.13,
1.5H), 0.98 (t, J ¼ 7.13, 1.5 H); 13C NMR (CDCl3) ꢀ 199.80, 171.52, 164.98,

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
4-ETHOXYCARBONYL PYRAZOLIN-5-ONE DERIVATIVES
3773
99.49, 62.45, 61.33, 27.57, 14.27, 14.17, 7.79; MS (ESI) (m/z) 217 [M þ H]þ,
161, 133, 104 (base peak); 239 [M þ Na]þ.
Diethyl pivaloylmalonate (2c): Rf ¼ 0.50 (10% ethyl acetate in
1
hexanes); IR (neat, NaCl) 3654, 2978, 1736, 1478, 1038 cmÀ1; H NMR[11c]
(CDCl3) ꢀ 4.83 (br s, 1H), 4.15 (q, J ¼ 7.12, 4H), 1.19 (q, J ¼ 7.12, 6H), 1.10
(s, 9H); 13C NMR (CDCl3) ꢀ 203.88, 165.01, 62.47, 60.05, 45.82, 26.13,
14.22; MS (m/z) 245 [M þ H]þ, 161, 84 (base peak); 267 [M þ Na]þ.
Diethyl cyclopentanecarbonylmalonate (2d): Rf ¼ 0.60 (15% ethyl ace-
tate in hexanes); IR (neat, NaCl) 3583, 2963, 1730, 1601, 1241, 1035 cmÀ1
;
1H NMR[11d] (CDCl3) ꢀ 13.28, 4.52 (br s, br s, total 1H), 4.22–4.23 (m, 4H),
3.05–2.90 (m, 1H), 1.78–1.52 (m, 8H), 1.27–1.18 (m, 6H); 13C NMR (CDCl3)
ꢀ 202.13, 171.43, 165.00, 99.54, 62.49, 61.48, 43.09, 31.34, 29.90, 26.74,
26.32, 14.56, 14.28; MS (ESI) (m/z) 257 [M þ H]þ, 202, 115, 96.55 (base
peak); 279 [M þ Na]þ.
Diethylcaproylmalonate (2e): Rf ¼ 0.50 (10% ethyl acetate in hexanes);
IR (neat, NaCl) 3584, 2959, 1734, 1602, 1243, 1040 cmÀ1; 1H NMR (CDCl3)
ꢀ 13.36, 4.43 (br s, br s, total 1H), 4.26–4.19 (m, 4H), 2.58 (t, J ¼ 7.30, 1H),
2.40 (t, J ¼ 7.30, 1H), 1.64–1.57 (m, 2H), 1.30–1.22 (m, 10H), 0.86 (t,
J ¼ 6.76, 3H); 13C NMR (CDCl3) ꢀ 199.37, 171.56, 165.04, 100.08, 62.59,
61.60, 34.11, 31.77, 26.83, 22.69, 14.45, 14.34, 14.21; MS (ESI) (m/z) 259
[M þ H]þ, 180, 135 (base peak); 281 [M þ Na]þ.
Diethyldecanoymlaolnate (2f ):
Rf ¼ 0.30 (15% ethyl acetate in
hexanes); IR (neat, NaCl) 2927, 1735, 1602, 1243, 1037 cmÀ1
;
1H NMR
(CDCl3) ꢀ 13.36, 4.43 (br s, br s, total 1H), 4.28–4.19 (m, 4H), 2.59 (t,
J ¼ 7.29, 1H), 2.41 (t, J ¼ 7.29, 1H), 1.64–1.57 (m, 2H), 1.31–1.21 (m, 18H),
0.86 (t, J ¼ 6.87, 3H); 13C NMR (CDCl3) ꢀ 199.39, 171.58, 165.05, 100.08,
62.61, 61.45, 34.19, 32.22, 29.77, 29.63, 27.17, 25.36, 23.76, 23.02, 14.61,
14.43, 14.33; MS (ESI) (m/z) 315 [M þ H]þ, 202, 161 (base peak); 104; 337
[M þ Na]þ.
Diethylbenzoylmalonate (2g): Rf ¼ 0.45 (20% ethyl acetate in hexanes);
IR (neat, NaCl) 3463, 3063, 1734, 1692, 1294, 1037 cmÀ1 1H NMR[11a]
;
(CDCl3) ꢀ 13.41, 5.28 (br s, br s, total 1H), 7.89–7.42 (m, 5H), 4.23 (q,
J ¼ 7.13, 4H), 1.23 (t, J ¼ 7.13, 6H); 13C NMR (CDCl3) ꢀ 189.36, 165.26,
135.80, 134.41, 129.07, 128.69, 62.75, 61.94, 14.40, 14.03; MS (ESI) (m/z)
265 [MþH]þ, 219, 104 (base peak); 287 [MþNa]þ.
Diethyl4-methoxybenzoyml aolnate (2h): Rf ¼ 0.50 (20% ethyl acetate
in hexanes); IR (neat, NaCl) 3651, 2983, 1735, 1600, 1028 cmÀ1 1H
;
1H NMR (CDCl3) ꢀ 13.35, 5.23 (br s, br s, total 1H), 7.83 (d, J ¼ 8.92,
2H), 6.88 (d, J ¼ 8.92, 2H), 4.20 (q, J ¼ 7.08, 4H), 3.78 (s, 3H), 1.19 (t,
J ¼ 7.08, 6H); 13C NMR (CDCl3) ꢀ 187.78, 165.43, 164.64, 134.33, 131.26,
125.65, 114.50, 62.58, 61.95, 55.90, 14.26; MS (ESI) (m/z) 295 [MþH]þ, 249,
135 (base peak); 317 [MþNa]þ.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3774
JUNG, WATKINS, AND AVERY
Diethyl 3-phenylpropionylmalonate (2i): Rf ¼ 0.50 (33% ethyl acetate
in hexanes); IR (neat, NaCl) 3584, 3031, 1731, 1650, 1243, 1037 cmÀ1
;
1H NMR[11c] (CDCl3) ꢀ 13.40, 4.58 (br s, br s, total 1H), 7.34–7.19 (m,
5H), 4.29–4.21 (m, 4H), 3.94, 3.80 (s, s, total 2H), 1.34–1.25 (m, 6H);
13C NMR (CDCl3) ꢀ 197.08, 171.53, 164.91, 135.90, 130.16, 129.51,
129.05, 128.62, 127.64, 100.78, 63.77, 61.70, 39.97, 14.50, 14.37; MS (ESI)
(m/z) 279 [MþH]þ, 202, 161 (base peak); 104, 90; 301 [MþNa]þ.
Diethyl hydrocinnamoylmalonate (2j): Rf ¼ 0.50 (20% ethyl acetate in
hexanes); IR (neat, NaCl) 3449, 3063, 1733, 1604, 1245, 1039 cmÀ1
;
1H NMR (CDCl3) ꢀ 13.50, 4.44 (br s, br s, total 1H), 7.31–7.17 (m, 5H),
4.28–4.17 (m, 4H), 2.99–2.59 (m, 4H), 1.33–1.21 (m, 6H); 13C NMR (CDCl3)
ꢀ 198.45, 171.64, 164.93, 140.99, 140.90, 140.79, 128.89, 128.72, 126.66,
100.42, 62.72, 61.36, 36.34, 31.38, 14.59, 14.33; MS (ESI) (m/z) 293
[MþH]þ, 247, 161 (base peak); 104; 315 [MþNa]þ.
Malonyldihydrazide (6): To a stirred solution of diethyl acetylmalonate
(3a, 5.0 g, 24.7 mmol) in ethanol, hydrazine (98%, 1.2 g, 36.7 mmol) was
added dropwise at room temperature.The reaction mixture was heated at
reflux for 3 h.After cooling, the solvent was evaporated, and the residue was
treated with diethyl ether (36 mL).The resulting solid was filtered and
washed with diethyl ether and then recrystallized from ethanol in diethyl
ether (v/v: 1/10) to give white crystals (1.5 g, 45%). Rf ¼ 0.25 (10% metha-
nol in dichlorohexane); m.p. 153ꢀC (lit.[12] m.p. 154ꢀC); IR (Nujol, NaCl)
1
3305, 2923, 1681, 1461, 1052 cmÀ1; H NMR (DMSO-d6) ꢀ 9.04 (br s, 2H),
4.22 (br s, 4H), 2.88 (s, 2H); 13C NMR (CDCl3) ꢀ 166.91, 39.68; MS (ESI)
(m/z) 133 [MþH]þ, 100 (base peak); 155 [MþNa]þ, also isolated was diethyl
malonate (1, 0.95 g, 24%).
GeneralProcedure for the Preparation of
4-Ethoxycarbonylpyrazolin-5-one Derivatives (3a–f )
Method A: To a stirred solution of a-acylated diethyl malonate (2,
20.0 mmol) in ethanol was added dropwise aqueous hydrazine solution
(pH ¼ 7, 30.0 mmol), [prepared by neutralizing hydrazine (55% aq. solution)
with 1 N HCl], at room temperature.The reaction mixture was heated at
reflux for 3–16 h.After cooling, the solvent was evaporated, and the residue
was treated with diethyl ether (35 mL).The resulting solid was filtered and
washed with diethyl ether and recrytallized from ethanol in diethyl ether
(v/v; 1/10) to give white crystals.
Method B: To a stirred solution of a-acylated diethyl malonates
(2, 20.0 mmol) in ethanol, hydrazine monohydrochloride (30.0 mmol) was
added portionwise at room temperature.The reaction mixture was heated

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
4-ETHOXYCARBONYL PYRAZOLIN-5-ONE DERIVATIVES
3775
at reflux for 3–16 h.After cooling, the solvent was evaporated, and the
residue was treated with diethyl ether (35 mL).The resulting solid was
filtered and washed with a small amount of water and diethyl ether and
then recrystallized from ethanol in diethyl ether (v/v; 1/10) to give white
crystals.
Method C: To a stirred solution of a-acylated diethyl malonates (2,
30.0 mmol) in acetic acid (16 mL), hydrazine (55%, 45.0 mmol) was added
dropwise at 10ꢀC.The reaction mixture was heated at reflux for 3 h.After
cooling, the solvent was evaporated, and the residue was treated with diethyl
ether (50 mL).The resulting solid was filtered and washed with diethyl ether
and then recrystallized from ethanol in diethyl ether (v/v; 1/10) to give white
crystals.
4-Ethoxycarbonyl-3-methylpyrazolin-5-one (3a): Rf ¼ 0.12 (5% metha-
nol in dichloromethane); m.p. 202ꢀC (lit.[6] 206–207ꢀC); IR (Nujol, NaCl)
3256, 2923, 1682, 1538, 1456, 1131 cmÀ1; 1H NMR (DMSO-d6) ꢀ 11.03 (br s,
2H), 4.12 (q, J ¼ 7.05, 2H), 2.28 (s, 3H), 1.21 (t, J ¼ 7.05, 3H); 13C NMR
(DMSO-d6) ꢀ 164.43, 161.91, 144.93, 95.65, 59.59, 15.19, 12.96; MS (ESI)
(m/z) 171 [MþH]þ, (base peak), 157, 143, 125.
4-Ethoxycarbonyl-3-ethylpyrazolin-5-one (3b): Rf ¼ 0.10 (5% methanol
in dichloromethane); m.p. 152ꢀC; IR (Nujol, NaCl) 3244, 2923, 1683, 1462,
1
1130 cmÀ1; H NMR (DMSO-d6) ꢀ 11.84 (br s, 2H), 4.13 (q, J ¼ 6.85, 2H),
2.70 (q, J ¼ 7.22, 2H), 1.20 (t, J ¼ 6.85, 3H), 1.11 (t, J ¼ 7.22, 3H);
13C NMR (DMSO-d6) ꢀ 163.38, 161.98, 150.42, 94.72, 59.63, 20.37, 15.12,
13.76; MS (ESI) (m/z) 185 [MþH]þ, 171, 157, 139 (base peak), 104; 207
[MþNa]þ.
4-Ethoxycarbonyl-3-pentylpyrazolin-5-one (3c): Rf ¼ 0.12 (10% metha-
nol in dichloromethane); m.p. 115–116ꢀC; IR (Nujol, NaCl) 3208, 2924,
1
1690, 1461, 1106 cmÀ1; H NMR (DMSO-d6) ꢀ 7.00 (br s, 2H), 4.12 (q,
J ¼ 7.10, 2H), 2.69 (t, J ¼ 7.56, 2H), 1.53 (t, J ¼ 6.77, 2H), 1.23–1.18 (m,
7H), 0.83 (t, J ¼ 2.50, 3H); 13C NMR (DMSO-d6) ꢀ 164.14, 161.55, 149.48,
95.13, 59.74, 31.70, 28.77, 26.64, 22.58, 15.11, 14.66; MS (ESI) (m/z) 227
[MþH]þ, (base peak), 181, 135; 249 [MþNa]þ.
4-Ethoxycarbonyl-3-nonylpyrazolin-5-one (3d): Rf ¼ 0.10 (5% metha-
nol in dichloromethane); m.p. 136ꢀC; IR (Nujol, NaCl) 3287, 2942, 1688,
1
1460, 1103 cmÀ1; H NMR (DMSO-d6) ꢀ 6.52 (br s, 2H), 4.13 (q, J ¼ 7.07,
2H), 2.68 (t, J ¼ 7.79, 2H), 1.53 (d, J ¼ 6.36, 2H), 1.23 ꢁ 1.19 (m, 15H), 0.82
(t, J ¼ 6.75, 3H); 13C NMR (DMSO-d6) ꢀ 164.32, 161.89, 149.17, 95.02,
59.64, 32.12, 29.74, 29.49, 29.13, 26.72, 22.93, 15.12, 14.76; MS (ESI)
(m/z) 283 [MþH]þ, (base peak), 255, 161, 104; 305 [MþNa]þ.
4-Ethoxycarbonyl-3-benzylpyrazolin-5-one (3e): Rf ¼ 0.16 (10% metha-
nol in dichloromethane); m.p. 146ꢀC; IR (Nujol, NaCl) 3203, 3062, 1725,
1685, 1461, 1107 cmÀ1; 1H NMR (DMSO-d6) ꢀ 8.87 (br s, 2H), 7.20–7.15 (m,

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3776
JUNG, WATKINS, AND AVERY
5H), 4.09 (q, J ¼ 7.10, 2H), 4.06 (s, 2H), 1.14 (t, J ¼ 7.10, 3H); 13C NMR
(DMSO-d6) ꢀ 163.80, 161.02, 147.93, 138.98, 129.15, 127.16, 95.37, 59.90,
32.23, 15.08; MS (ESI) (m/z) 247 [MþH]þ, 201, 133 (base peak), 89; 269
[MþNa]þ.
4-Ethoxycarbonyl-3-methylbenzylpyrazolin-5-one (3f ): Rf ¼ 0.11 (5%
methanol in dichloromethane); m.p. 131–132ꢀC; IR (Nujol, NaCl) 3329,
1
2923, 1686, 1456, 1102 cmÀ1; H NMR (DMSO-d6) ꢀ 7.28–7.13 (m, 5H),
6.96 (br s, 2H), 4.15 (q, J ¼ 7.07, 2H), 2.99 (dd, J ¼ 6.77, J ¼ 4.89, 2H),
2.85 (dd, J ¼ 5.28, J ¼ 6.57, 2H), 1.21 (t, J ¼ 7.07, 3H); 13C NMR (DMSO-
d6) ꢀ 164.07, 162.73, 161.27, 148.79, 141.63, 129.19, 129.02, 126.90, 95.28,
59.86, 35.11, 28.82, 15.20; MS (ESI) (m/z) 261 [MþH]þ, (base peak), 215,
161, 133; 283 [MþNa]þ.
Malonanilic acid ethyl ester (7a) and malonanilic acid hydrazide (7b): To
a stirred solution of ethyl 3-amino-2-phenylaminocarbonyl-2-butyrate (8,
1.7 g, 6.9 mmol) in ethanol was added dropwise hydrazine (80%, 0.4 g,
10.0 mmol) at room temperature. The reaction mixture was heated at reflux
for 3 h.After cooling, the solvent was evaporated, and the mixture was
separated by column chromatography on silica gel using 5% methanol in
dichloromethane to afford malonanilic acid ethyl ester (7a, 0.31 g, 22%)
and malonanilic acid hydrazide (7b, 0.83 g, 63%), respectively. Compound
7a: Rf ¼ 0.55 (3% methanol in dichloromethane); m.p. 38ꢀC (lit.[13] m.p.
38–39ꢀC); IR (Nujol, NaCl) 3286, 2951, 1640, 1461, 1376 cmÀ1; H NMR
1
(CDCl3) ꢀ 9.38 (s, 1H), 7.51–7.03 (m, 5H), 4.10 (q, J ¼ 7.12, 2H), 3.42
(s, 2H), 1.17 (t, J ¼ 7.12, 3H); 13C NMR (CDCl6) ꢀ 164.47, 159.97, 133.37,
124.50, 120.20, 115.97, 57.28, 38.41, 9.63. Compound 7b: m.p. 184ꢀC (lit.[14]
m.p. 183ꢀC); Rf ¼ 0.32 (5% methanol in dichloromethane); IR (Nujol,
NaCl) 3290, 2923, 1640, 1462, 1376, 1004 cmÀ1 1H NMR (DMSO-d6)
;
ꢀ 10.07 (br s, 1H), 9.18 (br s, 1H), 7.57–7.00 (m, 5H), 4.38 (s, 2H), 3.17
(s, 2H); 13C NMR (CDCl6) ꢀ 166.83, 166.30, 139.80, 129.60, 124.20,
119.91, 43.82.
Ethoxycarbonylacetohydrazide (8): To a stirred solution of ethyl
3-amino-2-ethoxycarbonyl-2-butyrate (5, 2.0 g, 10.0 mmol) in ethanol,
hydrazine (80%, 0.6 g, 15.0 mmol) was added dropwise at room tempera-
ture.The reaction mixture was heated at reflux for 3 h.After cooling, the
solvent was evaporated, and the mixture was separated by column chroma-
tography on silica gel using 2% methanol in dichloromethane to give a pale
yellow solid (0.45 g, 31%). Rf ¼ 0.33 (5% methanol in dichloromethane);
m.p. 70ꢀC (lit.[15] m.p. 68–69ꢀC); IR (Nujol, NaCl) 3299, 3044, 1731,
1
1462, 1004 cmÀ1; H NMR (CDCl3) ꢀ 8.20 (br s, 1H), 4.18 (q, J ¼ 7.11,
2H), 3.69 (br s, 2H), 3.31 (br s, 2H), 1.27 (t, J ¼ 7.11, 3H); 13C NMR
(CDCl3) ꢀ 169.90, 166.35, 62.16, 40.62, 14.41, also isolated was diethyl
malonate (1, 0.22 g, 14%).

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
4-ETHOXYCARBONYL PYRAZOLIN-5-ONE DERIVATIVES
ACKNOWLEDGMENT
3777
This publication was supported by Grant/Cooperative Agreement
Number UR3/CCU418652 from The Centers for Disease Control and
Prevention (CDC).
REFERENCES
1. Sugiura, S.; Ohno, S.; Ohtani, O.; Izumi, K.; Kitamikado, H.; Asai, H.;
Kato, K.; Hori, M.; Fujimura, H. J. Med. Chem. 1977, 20, 80.
2. (a) Kendall, J. D.; Duffin, G.F. U.S.P. 1955, 2, 704,762; (b) Reynolds,
G.A. U.S.P. 1954, 2, 688, 548.
3. Cativiela, C.; Serrano, J.L.; Zurbano, M.M. J. Org. Chem. 1995,
60, 3074.
4. Missio, L.J.; Braibante, H.S.; Braibante, M.E.F. J. Heterocyclic Chem.
1996, 33, 1243.
5. Al-Jallo, H.N.; Al-Khashab, A.; Sallomi, I.G. J. Chem. Soc. Perkin
Trans.1 1972, 1022.
6.Jursic, B; B. regant, NS.ynthC. ommun.
1989, 19, 2087.
7. Little, R.D.; Russu, W.A. J. Org. Chem. 2000, 65, 8096.
8. Braibante, M.E.F.; Braibante, H.S.; Missio, L.; Andricopulo, A.
Synthesis 1994, 9, 898.
9.Scavo, F; H. elquist, PT.etrahedron Lett.
1985, 26, 2603.
10. Perrin, D.D.; Armarego, L.F.; Perrin, D.R. Purification of Laboratory
Chemicals, 2nd Ed.; Peragmon Press: New York, 1980.
11. (a) Rathke, M.W.; Cowan, P.J. J. Org. Chem. 1985, 50, 2622; (b)
Bohman, O.; Allenmark, S. Acta Chem. Scand. 1968, 22, 2716; (c)
Skarzewski, J.Tetrahedron 1989, 45, 4593; (d) Sakai, T.; Amano, E.,
Kawabata, A.; Takeda, A. J. Org. Chem. 1980, 45, 43; (e) Schweizer,
E.E.; Lee, K.J. J. Org. Chem. 1982, 47, 2768.
12. Amanulla, S.; Jain, S.R. Indian J. Chem. 1997, 36B, 687.
13. Ukrainets, I.V.; Bezugly, P.A.; Treskach, V.I.; Taran, S.G.;
Gorokhova, O.V. Tetrahedron 1994, 50, 10331.
14.Ziegler, E; B. rus, GM. onatshC.hem.
67, 73567h.
1967, 98(3), 1100; Chem.Abstr.
15. Gallagher, M.J.; Jenkins, I.D. J. Chem. Soc., Perkin Trans. 1 1971,
208.
Received in the USA December 7, 2002

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.