Synthesis and cyclization reaction of pyrazolin-5-one derivatives

Article abstract of DOI:10.3987/COM-04-10216

A versatile synthetic method for preparing 3-pyrazolin-5-ones and 5,8-dihydro-1H-pyrazolo[1,2-a]pyridazines from simple β-keto esters is demonstrated. The synthetic strategies involve the acylation of β-keto esters, cyclocondensation with hydrazine followed by trapping with a diene under oxidative conditions.

Full text of DOI:10.3987/COM-04-10216

HETEROCYCLES, Vol. 65, No. 1, 2005
77
HETEROCYCLES, Vol. 65, No. 1, 2005, pp. 77 - 94
Received, 31st August, 2004, Accepted, 1st November, 2004, Published online, 2nd November, 2004
SYNTHESIS AND CYCLIZATION REACTION OF PYRAZOLIN-5-ONE
DERIVATIVES
Jae-Chul Jung,a E. Blake Watkins,a and Mitchell A. Avery*a,b,c
aDepartment of Medicinal Chemistry, School of Pharmacy,
bDepartment of Chemistry and Biochemistry,
cNational Center for Natural Products Research, University of Mississippi, P.O.
Box 1848, University, MS 38677–1848, USA
E-mail: mavery@olemiss.edu
Abstract–A versatile synthetic method for preparing 3-pyrazolin-5-ones and 5,8-
dihydro-1H-pyrazolo[1,2-a]pyridazines from simple β−keto esters is
demonstrated. The synthetic strategies involve the acylation of β−keto esters,
cyclocondensation with hydrazine followed by trapping with a diene under
oxidative conditions.
INTRODUCTION
Pyrazolinones are an interesting group of compounds, many of which possess widespread
pharmacological properties1 such as analgesic, antipyretic, antiphlogistic, antiarthritic, uricosuric,
antirheumatic, and antiinflammatory activities. Furthermore, they are potentially useful intermediates for
many industrial products and agrochemical applications such as color photography,2 dyestuffs,3 liquid
crystals,4 and herbicides.5 Chemically, pyrazolinones are known to undergo oxidation with PhI(OAc)2,6
8
Tl(NO3)3,7 and Pb(OAc)4 to give, respectively, general 2-alkynoates, 2,3-alkadienoates and the unstable
pyrazol-3-ones, which are azo dienophiles and, as such, may be trapped as cycloadducts in the presence of
1,3-dienes.9
Our continuing interest in the chemistry of pyrazolin-5-ones relates in part to their potential use as
scaffolds in combinatorial chemistry. A variety of routes for the synthesis of substituted pyrazolin-5-ones
have been reported in the literature.10 Most of these methods are based on 1,3-diketo ring-cyclizations
with hydrazine or substituted hydrazines. Yields vary from substrate to substrate and from method to
method. Our previous work has examined the scope and efficiency of pyrazolin-5-one synthesis.11 This
paper focuses on the chemistry of these compounds, namely on their abilities to act as azadienophiles in
Diels-Alder cycloaddition reactions.

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HETEROCYCLES, Vol. 65, No. 1, 2005
RESULTS AND DISCUSSION
The necessary α−acylated esters (3a-n) could easily be obtained, in high yields, by treatment of ethyl
acetoacetate (1a), ethyl cyanoacetate (1b) or diethyl malonate (1c) with the appropriate acyl chlorides (2)
in the presence of magnesium/ethanol in anhydrous toluene (Table 1).
Table 1. Acylation of ethyl acetoacetate (1a), ethyl cyanoacetate (1b) and diethyl malonate (1c).
O
O
Mg, EtOH
R1
R1
R2
OEt
R2-COCl
2
CO2Et
3
1
Products
(K/E)b
Entry
Compound
1a
R1
R2
Yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
COMe
COMe
COMe
CN
CN
CN
CN
CN
CN
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Me
(CH2)4CH3
Bz
91
98
94
90
84
81
86
88
85
82
88
87
89
84
3a12a (nd)c
3b12b (nd)
3c12c (nd)
1b
Me
3d12d (0/100)
3e (nd)
c-C3H5
c-C5H9
2-Thienyl
Ph
4-MeOC6H4
Me
3f (nd)
3g12e (0/100)
3h12d (0/100)
3i12f (0/100)
3j12g (29/71)
3kh (50/50)
3l12i (39/61)
3m12j (37/63)
3n12k (42/58)
1c
Et
(CH2)4CH3
(CH2)8CH3
CH2-Bz
aIsolated yields: in the case of ethyl cyanoacetate (Entries 4−9), the yields were
calculated based on recovered starting material. Keto−enol ratios based on integration
b
of 1H−NMR. nd=not determined.
c
The α−acylated ethyl acetoacetates were ring cyclized by treatment with hydrazine (80%) in ethanol;
while the α−acylated diethyl malonates were treated with hydrazine (pH 7),13 hydrazine (55%) in acetic
acid or hydrazine monohydrochloride to give the desired pyrazolin-5-ones in good yields. We have
shown previously that, in general, under these conditions ring cyclization proceeds smoothly for those
α−acylated esters or diesters that exist primarily in the enol form. Compounds with aromatic substituents
that exist predominately in the keto form rapidly undergo β−cleavage (retro aldol) to give either low yield
or no yield of the desired pyrazolin-5-one. On the other hand, ethyl cyanoacetate (1b) underwent
acylation with several acyl chlorides to afford α−acylated products, which exist completely in the enol
form (Table 1, Entries 4 and 7−9).14

HETEROCYCLES, Vol. 65, No. 1, 2005
79
Diethyl acetylmalonate (3j) could also be cyclized with p-toluenesulfonyl hydrazide in ethanol to give
ethyl 5-methyl-2-[4-methylphenylsulfonyl]-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (5), regioselec-
tively. The corresponding regioisomer (6c) was obtained by treating 4b with tosyl chloride. Furthermore,
the bis-tosylated derivative (6e) was easily formed in the presence of triethyl amine using 2 eq. of tosyl
chloride. Ring bromination was carried out by treatment of 4a or 6b with NBS to give the corresponding
products in good yield (Scheme 1).
O
O
R1
R1
R3
a
NH
NH
N
b
3
N
R4
4a R1=H
b R1=CO2Et
6a R1=H, R3=R4=CO2Et
b R1=R3=H, R4=Ts
c R1=CO2Et, R3=H, R4=Ts
d R1=R3=R4=CO2Et
e R1=CO2Et, R3=R4=Ts
c
e
d
O
O
O
O
Br
Br
Br
Ts
NH
EtO
N
NH
N
N
NH
R4
5
7
8
a R4=H
b R4=Ts
Scheme 1. Reagents and conditions: (a) Method A: H2NNH2 (80%)/EtOH; Method B: H2NNH2 (pH=7),
EtOH/H2O; Method C: H2NNH2 (55%)/HOAc; Method D: H2NNH2⋅HCl/EtOH; (b) Method A: ClCO2Et,
TEA/CH2Cl2; Method B: TsCl, TEA/CHCl3; (c) H2NNH-Ts/HOAc; (d) NBS, pyridine/CH2Cl2; (e) NBS,
NaH (60%)/THF.
Having completed the synthesis of the necessary pyrazolin-5-ones, we turned our attention to their role as
azadienophiles in the Diels-Alder cycloaddition reaction. It has been shown that pyrazolin-5-one could
be induced to undergo Diels-Alder reactions at nitrogen upon treatment with Pb(OAc)4. The reaction
proceeds through the highly unstable pyrazol-3-one,15 which is trapped by treatment with the appropriate
diene.
We tried unsuccessfully to generate and isolate the unstable pyrazol-3-one using numerous oxidative
conditions including Ag2O/dichloromethane,16a SiO2/NaNO2/oxalic acid dihydrate,16b-c K3Fe(CN)6
EtOH,16d PhCO2I(OAc)2,6 NBS/NaH(60%),16a KClO3/FeSO4/acetone,16e FeCl3⋅6H2O/2N-H2SO4/ace-
tone,16f DDQ/dichloromethane,16a NaOCl/acetone,16a 10% Pd-C/EtOH, In(OAc)3/dichloromethane,
Mn(OAc)3/dichloromethane and KMnO4/acetone,16a but these reactions were all unsatisfactory, and for
the most part, starting material was recovered. Given, et al. reported the lifetime for 2,3-diaza-2,4-
cyclopentadienone, a related compound, to be 63.5 ± 0.5 sec.10j Based on this report, it seemed unlikely

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HETEROCYCLES, Vol. 65, No. 1, 2005
that the pyrazol-3-ones investigated here would be isolable. Therefore, in the present study we treated
two pyrazolin-5-ones with lead (IV)acetate in dichloromethane at room temperature followed by
numerous dienes (Scheme 2) and isolated the reaction products (Table 2).
Pyrazolin-5-ones (4a) and (4b) were treated with Pb(OAc)4 in dichloromethane in the presence of
symmetrical or unsymmetrical dienes at –10 °C to give the hetero-Diels-Alder products shown in Scheme
2. The results of cyclization with isoprene, 1-methoxy-1,3-butadiene, 1-acetoxy-1,3- butadiene, 2,3-
dimethyl-1,3-butadiene, 2,5-dimethyl-2,4-hexadiene, 1,4-diphenyl- 1,3-butadiene, and 2,3-dibenzyl-1,3-
butadiene are shown in Table 2. Unsymmetrical dienes each gave a mixture of two products. Based on
NMR spectroscopy, compounds (10a:11a) were formed in a 45:55 ratio and 10g:11g were formed in a
42:58 ratio, while 10b:11b were formed in a 20:80 ratio. We were unable to determine the product ratios
R
1
O
O
O
R
2
R
N
N
Pb(OAc)4/CH2Cl2
N
N
NH
NH
R
+
R
R1
R2
R3
R2
R1
4a R=H
b R=CO Et
R
4
11
2
10
R
3
R4
9
Scheme 2
Table 2. Diels-Alder reactions of 4a and 4b
Time
(h)
3
Yield
(%)a
73
Entry
R
H
R1
H
R2
Me
H
R3
H
R4
H
Product
10a, 11a
10b, 11b
10c
1
2
H
OMe
H
H
H
3
1
1
1
1
3
3
1
1
1
1
31
85
81
74
78
82
36
92
89
75
80
3
H
Me
H
Me
H
4
H
(Me)2
Ph
H
H
(Me)2
Ph
H
10d
5
H
H
10e
6
H
H
Bz
Me
H
Bz
H
10f
7
CO2Et
H
H
10g, 11g
10h, 11h
10i
8
CO2Et OAc
CO2Et
CO2Et (Me)2
H
H
9
H
Me
H
Me
H
H
10
11
12
(Me)2
Ph
H
10j
CO2Et
CO2Et
Ph
H
H
H
10k
Bz
Bz
10l
a Isolated yields.

HETEROCYCLES, Vol. 65, No. 1, 2005
81
of 10h:11h. The low yields associated with Entries 2 and 8 (Table 2) result from the unstable nature of
the dienes under the given reaction conditions. Diels-Alder cyclization with silyloxydienes gave no yield
due to their inherent acid sensitivity.
Interestingly, when 4b was treated with Pb(OAc)4 in CH2Cl2 in the absence of a diene at –5oC and
warmed to room temperature, the isolated products were regioisomeric biamines, pyrazolo[1,2-a]-
pyrazole-2,6-dicarboxylates (13 and 14), (Scheme 3). Compound (13) is strongly fluorescent, while
compound (14) is strongly phosphorescent.17
O
O
O
O
EtO2C
Pb(OAc)4
CH2Cl2
N
N
N
N
N
4b
EtO2C
CO2Et
EtO2C
CO2Et
+
N
O
12
13
14
Scheme 3
On the other hand, when compound (10b) or (11b) was treated with potassium carbonate in methanol a
mixture of 3-methyl-1H-pyrazolo[1,2-a]pyridazin-1-one (15)18 and 7-methoxy-3-methyl- 7,8-dihydro-
1H-pyrazolo[1,2-a]pyridazin-1-one (16a) / 6-methoxy-3-methyl-5,6-dihydro-1H-pyrazolo[1,2-a]pyrida-
zin-1-one (16b) were isolated in 16% and 42% yields, respectively (Scheme 4). The ratio of 16a to 16b
was determined to be 78:22 by the integration of the methoxy group signals in the 1H−NMR spectrum.
O
O
O
OMe
N
N
N
N
N
N
K2CO3/MeOH
reflux 3 h
+
10b or 11b
+
OMe
15
16b
16a
Scheme 4
In an effort to improve the yield of pyridazine (15), several additional acid or base reaction conditions
were attempted, including DBU/dichloromethane, pyridine/dichloromethane, K2CO3/dichloromethane,
and BF3·Et2O/dichloromethane. Unfortunately, these reactions failed to afford 15, giving starting material
and/or decomposed products.
In conclusion, we report a versatile synthetic method for preparing 3-pyrazolin-5-one and 5,8-dihydro-
1H-pyrazolo[1,2-a]pyridazine compounds from simple β−keto esters. The synthetic strategies involve

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HETEROCYCLES, Vol. 65, No. 1, 2005
acylation, cyclocondensation, and oxidation-cycloaddition. The key intermediates were 3-pyrazolin-5-
ones (4a) and (4b), which could be transformed to 5,8-dihydro-1H-pyrazolo[1,2-a]pyridazines (10a-l),
(11a-b), (11g-h) and pyrazolo[1,2-a]pyrazole- 2,6-dicarboxylates (13) and (14) through the trapping of a
highly reactive, but unstable intermediate (12).
EXPERIMENTAL
Reactions requiring anhydrous conditions were performed with the usual precautions for rigorous
exclusion of air and moisture. Tetrahydrofuran was distilled from sodium benzophenone ketyl prior to use.
Thin layer chromatography (TLC) was performed on precoated silica gel G and GP uniplates from
Analtech and visualized with a 254-nm UV light. Flash chromatography was carried out on silica gel 60
[Scientific Adsorbents Incorporated (SAI), particle size 32-63 µm, pore size 60 Å]. Melting points were
1
13
measured on a MEL-TEMP II apparatus and uncorrected. H NMR and C NMR spectra were recorded
on a Bruker DPX 300 at 300 MHz and 76 MHz, respectively. The chemical shifts were reported in parts
per million (ppm) downfield from tetramethylsilane, and J-values were in Hz. IR spectra were obtained
on an ATI Mattson FT/IR spectrometer. MS spectrum were recorded with a Waters Micromass ZQ LC-
Mass system and high resolution mass spectra (HRMS) were measured with a Bruker BioApex FTMS
system by direct injection using an electrospray interface (ESI). When necessary, chemicals were purified
according to the reported procedures.19
General Procedure for the Preparation of α−Acylated Ethyl Acetoacetates (3a−c), Ethyl
Cyanoacetate (3d−i), and Diethyl Malonates (3j−3n)
A mixture of ethyl acetoacetate (1.56 g, 12.0 mmol), ethyl cyanoacetate (1.36 g, 12.0 mmol), or diethyl
malonate (1.92 g, 12.0 mmol), magnesium (0.29 g, 12.1 mmol), ethanol (1.84 g, 40.0 mmol), carbon
tetrachloride (0.3 mL) and anhydrous toluene (30 mL) was stirred under argon at rt for 30 min. The
reaction was vigorously exothermic. The mixture was refluxed for 1 h and then cooled to 0–5°C. The
acylating reagent (12.1 mmol) was added dropwise to the solution at 0–5°C for 30 min, and the reaction
mixture was stirred at rt for 1 h. The resulting mixture was re-cooled to 0–5°C and washed with cold 5%
aq. hydrochloric acid solution (24 mL), sat’d sodium bicarbonate solution (24 mL) and brine (24 mL).
The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure
to give pale yellow liquids. The compounds were purified using silica gel and ethyl acetate/hexanes as
indicated.

HETEROCYCLES, Vol. 65, No. 1, 2005
83
Ethyl 2-acetyl-3-oxobutanoate (3a)
Rf=0.4 (10% ethyl acetate in hexanes); pale yellow oil; IR (neat, NaCl) 2984, 1713, 1416, 1084 cm-1; 1H
13
NMR (CDCl3) δ 15.86 (s, 1H), 4.20 (q, J=7.2 Hz, 2H), 2.30 (s, 6H), 1.27 (q, J=7.2 Hz, 3H); C NMR
(CDCl3) δ 196.9, 167.4, 109.0, 61.0, 26.2, 14.5; MS (ESI) (m/z) 173 [M+H]+, 127, 85 (base peak); 195
[M+Na]+.
Ethyl 2-acetyl-3-oxooctanoate (3b)
Rf =0.5 (10% ethyl acetate in hexanes); pale yellow oil; IR (neat, NaCl) 2934, 1714, 1416, 1709 cm-1; 1H
NMR (CDCl3) δ 4.21 (q, J=7.1 Hz, 2H), 2.63−2.58 (m, 2H), 2.29 (s, 3H), 1.67−1.49 (m, 2H), 1.32−1.27
13
(m, 7H), 0.84 (t, J=3.1 Hz, 3H); C NMR (CDCl3) δ 199.8, 196.0, 167.6, 109.0, 61.0, 38.1, 31.9, 25.9,
22.7, 14.5, 14.2; MS (ESI) (m/z) 229 [M+H]+, 183 (base peak), 135, 85; 251 [M+Na]+.
Ethyl 2-acetyl-3-oxo-4-phenylbutanoate (3c)
Rf =0.5 (20% ethyl acetate in hexanes); pale yellow oil; IR (neat, NaCl) 3405, 3031, 1714, 1414, 1239,
1
1080 cm-1; H NMR (CDCl3) δ 7.30−7.27 (m, 5H), 4.31−4.23 (m, 2H), 4.04 (s, 2H), 2.34 (s, 3H),
1.35−1.27 (m, 3H); 13C NMR (CDCl3) δ 196.7, 196.2, 167.3, 135.4, 129.8, 128.9, 127.3, 109.1, 61.2, 44.2,
25.9, 14.5; MS (ESI) (m/z) 249 [M+H]+, 207, 131, 91 (base peak); 271 [M+Na]+.
Ethyl 2-cyano-3-oxobutanoate (3d)
Rf =0.3 (ethyl acetate:hexane:methanol; 40:50:10, v/v); beige oil; IR (neat, NaCl) 2987, 2226, 1660, 1278,
1
1065 cm-1; H NMR (CDCl3) δ 13.50 (s, 1H), 4.27 (q, J=7.2 Hz, 2H), 2.29 (s, 3H), 1.30 (t, J=7.2 Hz,
3H); 13C NMR (CDCl3) δ 189.6, 170.3, 115.1, 81.5, 60.9, 21.1, 13.7; HRMS Calcd for C7H9NO3Na:
178.0480 [M+Na]+, Found: 178.0304.
Ethyl 2-cyano-3-cyclopropyl-3-oxopropanoate (3e)
Rf =0.3 (ethyl acetate:hexane:methanol; 40:50:10, v/v); mp 68°C (Et2O:hexane, 1:10, v/v); IR (neat, NaCl)
2946, 2222, 1683, 1577, 1280 cm-1; 1H NMR (CDCl3) δ 4.30 (q, J=7.2 Hz, 2H), 2.21–2.13 (m, 1H), 1.36
(t, J=7.2 Hz, 3H), 1.30–1.26 (m, 2H), 1.18–1.15 (m, 2H); 13C NMR (CDCl3) δ 191.4, 170.5, 115.6, 79.2,
62.3, 15.3, 14.1, 11.2; HRMS Calcd for C9H11NO3Na: 204.0637 [M+Na]+, Found: 204.0294. Anal. Calcd
for C, 59.66; H, 6.12; N, 7.73. Found: C, 59.51; H, 5.95; N, 7.72.
Ethyl 2-cyano-3-cyclopentyl-3-oxopropanoate (3f)
Rf =0.3 (ethyl acetate:hexane:methanol; 40:50:10, v/v); pale yellow oil; IR (neat, NaCl) 2962, 2225, 1654,

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HETEROCYCLES, Vol. 65, No. 1, 2005
1
1591, 1277, 1045 cm-1; H NMR (CDCl3) δ 4.30 (q, J=7.2 Hz, 2H), 2.72–2.64 (m, 1H), 1.89–1.61 (m,
13
8H), 1.34 (t, J=7.2 Hz, 3H); C NMR (CDCl3) δ 194.7, 170.5, 115.1, 79.8, 62.4, 44.1, 30.9, 30.0, 26.4,
25.8, 14.2.
Ethyl 2-cyano-3-oxo-3-(2-thienyl)propanoate (3g)
Rf =0.5 (ethyl acetate:hexane:methanol; 40:50:10, v/v); pale yellow oil; IR (neat, NaCl) 2984, 2359, 1653,
1575, 1278, 1063 cm-1; 1H NMR (CDCl3) δ 14.28 (s, 1H), 7.85–7.75 (m, 2H), 7.25–7.18 (m, 1H), 4.38 (q,
J=7.2 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3) δ 174.8, 162.9, 137.7, 134.6, 134.4, 128.7,
116.2, 75.6, 63.0, 14.1.
Ethyl 2-cyano-3-oxo-3-phenylpropanote (3h)
Rf =0.4 (ethyl acetate:hexane:methanol; 40:50:10, v/v); mp 32°C (Et2O:hexane, 1:10, v/v); IR (neat, NaCl)
2986, 2229, 1678, 1580, 1247, 1058 cm-1; 1H NMR (CDCl3) δ 14.30 (s, 1H), 8.01 (d, J=7.6 Hz, 2H), 7.59
(t, J=7.6 Hz, 1H), 7.50 (t, J=7.2 Hz, 2H), 4.41 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H); 13C NMR
(CDCl3) δ 185.4, 170.8, 133.8, 131.5, 128.9, 115.5, 79.3, 61.5, 13.8; HRMS Calcd for C12H12NO3:
218.0817 [M+H]+, Found: 218.0809.
Ethyl 2-cyano-3-oxo-3-(4-methoxyphenyl)propanote (3i)
Rf =0.5 (ethyl acetate:hexane:methanol; 40:50:10, v/v); pale yellow oil; IR (neat, NaCl) 3395, 2983, 2219,
1
1683, 1559, 1261, 1025 cm-1; H NMR (CDCl3) δ 14.26 (s, 1H), 7.03–7.90 (m, 4H), 4.30 (q, J=7.2 Hz,
13
2H), 3.46 (s, 3H), 1.31 (t, J=7.2 Hz, 3H); C NMR (CDCl3) δ 182.1, 171.7, 163.7, 132.3, 131.6, 130.9,
116.6, 114.0, 113.6, 63.0, 60.4, 55.5, 14.1.
Diethyl 2-acetylmalonate (3j)
Rf=0.5 (20% ethyl acetate in hexanes); pale yellow oil; IR (neat, NaCl) 2984, 1729, 1650, 1469, 1090 cm-1;
1H NMR (CDCl3) δ 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) δ 197.0, 171.6, 166.4, 100.2, 62.2, 61.4, 21.0, 14.4, 14.3; MS
(ESI) (m/z) 203 [M+H]+, 179, 157 (base peak); 225 [M+Na]+.
Diethyl 2-propionylmalonate (3k)
Rf=0.6 (20% ethyl acetate in hexanes); pale yellow oil; IR (neat, NaCl) 3443, 2984, 1734, 1604, 1034
1
cm-1; H NMR (CDCl3) δ 13.31, 4.37 (br s, br s, total 1H), 4.17−4.07 (m, 4H), 2.53 (q, J=7.1 Hz, 1H),
2.35 (q, J=7.1 Hz, 1H), 1.21−1.15 (m, 6H), 1.08 (t, J=7.1 Hz, 1.5H), 0.98 (t, J=7.1 Hz, 1.5H); 13C NMR

HETEROCYCLES, Vol. 65, No. 1, 2005
85
(CDCl3) δ 199.8, 171.5, 165.0, 99.5, 62.5, 61.3, 27.6, 14.3, 14.2, 7.8; MS (ESI) (m/z) 217 [M+H]+, 161,
133, 104 (base peak); 239 [M+Na]+.
Diethyl 2-hexanoylmalonate (3l)
Rf =0.5 (10% ethyl acetate in hexanes); pale yellow oil; IR (neat, NaCl) 3584, 2959, 1734, 1602, 1243,
1
1040 cm-1; H NMR (CDCl3) δ 13.36, 4.43 (br s, br s, total 1H), 4.26−4.19 (m, 4H), 2.58 (t, J=7.3 Hz,
13
1H), 2.40 (t, J=7.3 Hz, 1H), 1.64−1.57 (m, 2H), 1.30−1.22 (m, 10H), 0.86 (t, J=6.8 Hz, 3H); C NMR
(CDCl3) δ 199.4, 171.6, 165.0, 100.1, 62.6, 61.6, 34.1, 31.8, 26.8, 22.7, 14.5, 14.3, 14.2; MS (ESI) (m/z)
259 [M+H]+, 180, 135 (base peak); 281 [M+Na]+.
Diethyl 2-decanoylmalonate (3m)
Rf=0.3 (15% ethyl acetate in hexanes); pale yellow oil; IR (neat, NaCl) 2927, 1735, 1602, 1243, 1037
1
cm-1; H NMR (CDCl3) δ 13.36, 4.43 (br s, br s, total 1H), 4.28−4.19 (m, 4H), 2.59 (t, J=7.3 Hz, 1H),
2.41 (t, J=7.3 Hz, 1H), 1.64−1.57 (m, 2H), 1.31−1.21 (m, 18H), 0.86 (t, J=6.9 Hz, 3H); 13C NMR
(CDCl3) δ 199.4, 171.6, 165.1, 100.1, 62.6, 61.5, 34.2, 32.2, 29.8, 29.6, 27.2, 25.4, 23.8, 23.0, 14.6, 14.4,
14.3; MS (ESI) (m/z) 315 [M+H]+, 202, 161 (base peak), 104; 337 [M+Na]+.
Diethyl 2-(3-phenylpropionyl)malonate (3n)
Rf=0.5 (20% ethyl acetate in hexanes); pale yellow oil; IR (neat, NaCl) 3449, 3063, 1733, 1604, 1245,
1
1039 cm-1; H NMR (CDCl3) δ 13.50, 4.44 (br s, br s, total 1H), 7.31−7.17 (m, 5H), 4.28−4.17 (m, 4H),
13
2.99−2.59 (m, 4H), 1.33−1.21 (m, 6H); C NMR (CDCl3) δ 198.5, 171.6, 164.9, 141.0, 140.9, 140.8,
128.9, 128.7, 126.7, 100.4, 62.7, 61.4, 36.3, 31.4, 14.6, 14.3; MS (ESI) (m/z) 293 [M+H]+, 247, 161 (base
peak), 104; 315 [M+Na]+.
Ethyl 5-methyl-2-[4-methylphenylsulfonyl]-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (5)
To a solution of diethyl 2-acetylmalomate (1.0 g, 5.0 mmol), p−toluenesulfonyl hydrazide (1.0 g, 5.0
mmol) in ethanol (6 mL) was added acetic acid (1 mL), and the mixture was refluxed for 16 h. The
reaction mixture was concentrated under reduced pressure, and the residue was treated with ethanol/ether
(5 mL, v/v, 1:9). The solid was filtered and washed with ether (6 mL) to give 5 (1.3 g, 81%). Rf=0.1 (10%
methanol in dichloromethane); mp 155°C (EtOH:Et2O, 1:10, v/v); IR (nujol, NaCl) 3271, 2953, 1687,
1
1462, 1377, 1170 cm-1; H NMR (DMSO−d6) δ 9.92 (br s, 1H), 7.75−7.39 (m, 4H), 4.12 (q, J=7.1 Hz,
2H), 2.31 (s, 3H), 2.24 (s, 3H), 1.21 (t, J=7.1 Hz, 3H); 13C NMR (DMSO−d6) δ 164.3, 161.7, 145.1,

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138.7, 135.2, 130.7, 129.0, 128.7, 126.4, 95.7, 59.7, 21.8, 15.2, 13.0; HRMS Calcd for C14H17N2O5S:
325.0853 [M+H]+, Found: 325.0851.
General Procedure for the Preparation of N-Substituted 3-Pyrazolin-5-one Derivatives (6a−e)
Method A. A solution of ethyl chloroformate (2.39 g, 22.0 mmol) in dichloromethane (5 mL) was added
dropwise to a suspension of pyrazolin-5-one compounds (10.0 mmol) and triethylamine (2.43 g, 24.0
mmol) in dry dichloromethane (50 mL) at 10oC under an argon atmosphere. The reaction mixture was
stirred at rt for 3 h. The mixture was filtered and the filtrate was washed with water (20 mL) and brine (20
mL). The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The
residue was chromatographed on silica gel (2–5% methanol in dichloromethane) to give products.
Method B. To a stirred solution of pyrazolin-5-one compounds (10.0 mmol), triethylamine (1.11 g, 11.0
mmol or 2.23 g, 22.0 mmol) in chloroform (50 mL) was added dropwise a solution of p-toluenesulfonyl
o
chloride (2.10 g, 11.0 mmol or 4.19 g, 22.0 mmol) in dried chloroform (5 mL) at 5 C under an argon
atmosphere. The reaction mixture was stirred at rt for 3 h. The mixture was extracted with
dichloromethane and washed with 5% aq. HCl solution (20 mL) and sat’d NaHCO3 solution (20 mL).
The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The
residue was chromatographed on silica gel (2–5% methanol in dichloromethane) to give white crystals.
Diethyl 5-methyl-3-oxo-1H-pyrazole-1,2(3H)-dicarboxylate (6a)
Yield; 83%; Rf=0.7 (5% methanol in dichloromethane); oil; IR (neat, NaCl) 2984, 1769, 1754, 1580,
1
1239 cm-1; H NMR (CDCl3) δ 6.01 (br s, 1H), 4.44 (q, J=7.1 Hz, 2H), 4.26 (q, J=7.1 Hz, 2H), 2.51 (s,
3H), 1.41 (t, J=7.1 Hz, 3H), 1.31 (t, J=7.1 Hz, 3H); 13C NMR (CDCl3) δ 157.2, 152.3, 150.3, 146.6, 110.0,
102.2, 65.8, 64.8, 15.0, 14.6; MS (ESI) (m/z) 243 [M+H]+, 171, 98 (base peak); 265 [M+Na]+; HRMS
Calcd for C10H14N2O5Na: 265.0795 [M+Na]+, Found: 265.0793.
5-Methyl-1-[4-methylphenylsulfonyl]-1,2-dihydro-3H-pyrazol-3-one (6b)
Yield; 65%; Rf=0.3 (2% methanol in dichloromethane); mp 109°C [purified by FC (CH2Cl2:MeOH, 98:2,
v/v)]; IR (nujol, NaCl) 3195, 2924, 1579, 1461, 1197 cm-1; 1H NMR (CDCl3) δ 11.24 (br s, 1H), 7.76 (d,
J=8.3 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 5.67 (s, 1H), 242 (s, 3H), 2.23 (s, 3H); 13C NMR (CDCl3) δ 163.2,
156.9, 141.0, 135.8, 130.3, 125.4, 95.3, 21.8, 20.9; HRMS Calcd for C11H12N2O3NaS: 275.0461 [M+Na]+,
Found: 275.0454.

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87
Ethyl 5-methyl-1-[4-methylphenylsulfonyl]-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (6c)
Yield; 67%; Rf=0.5 (5% methanol in dichloromethane); mp 134°C [purified by FC (CH2Cl2:MeOH, 98:2,
v/v)]; IR (nujol, NaCl) 2923, 1692, 1457, 1377 cm-1; 1H NMR (CDCl3) δ 11.14 (br s, 1H), 7.82 (d, J=8.3
Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 4.22 (q, J=7.1 Hz, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 1.31 (t, J=7.1 Hz, 3H);
13C NMR (CDCl3) δ 162.4, 153.5, 146.6, 146.0, 133.4, 130.1, 128.9, 102.5, 60.7, 22.1, 14.6, 12.4; HRMS
Calcd for C14H17N2O5S: 325.0853 [M+H]+, Found: 325.0841. Anal. Calcd for C, 51.84; H, 4.97; N, 8.64.
Found: C, 52.10; H, 4.87; N, 8.65.
1,2,4-Triethoxycarbonyl-3-methylpyrazolin-5-one (6d)
Yield; 80%; Rf =0.6 (2% methanol in dichloromethane); mp 40°C [purified by FC (CH2Cl2:MeOH, 98:2,
1
v/v)]; IR (nujol, NaCl) 2985, 1776, 1717, 1584, 1237 cm-1; H NMR (CDCl3) δ 4.45−4.21 (m, 6H), 2.83
(s, 3H), 1.41−1.24 (m, 9H); 13C NMR (CDCl3) δ 161.7, 155.9, 152.1, 151.8, 149.8, 106.9, 66.0, 65.5, 61.0,
14.5, 14.4, 13.9; HRMS Calcd for C13H18N2O7Na: 337.1006 [M+Na]+, Found: 337.1001. Anal. Calcd for
C, 49.68; H, 5.77; N, 8.91. Found: C, 49.99; H, 5.61; N, 8.93.
Ethyl 5-methyl-1,2-bis[4-methylphenylsulfonyl]-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (6e)
Yield; 77%; Rf=0.8 (5% methanol in dichloromethane); mp 79°C [purified by FC (CH2Cl2:MeOH, 95:5,
1
v/v)]; IR (nujol, NaCl) 2922, 1723, 1462, 1377 cm-1; H NMR (CDCl3) δ 7.78−7.75 (m, 4H), 7.34−7.25
(m, 4H), 4.28 (q, J=9.1 Hz, 2H), 2.82 (s, 3H), 2.48 (s, 3H), 2.46 (s, 3H), 1.33 (t, J=7.1 Hz, 3H); 13C NMR
(CDCl3) δ 162.7, 146.9, 130.5, 130.0, 129.2, 128.7, 61.5, 22.2, 14.5, 12.7; HRMS Calcd for
C21H22N2O7S2Na: 501.0760 [M+Na]+, Found: 501.0771.
4,4-Dibromo-5-methyl-2,4-dihydro-3H-pyrazol-3-one (7)
To a solution of 3-methyl-3-pyrazolin-5-one (0.5 g, 5.1 mmol) and pyridine (1.6 g, 20.4 mmol) in
dichloromethane (20 mL) was added N−bromosuccinimide (2.7 g, 15.3 mmol) under an argon atmosphere,
and the mixture was stirred at rt for 5 h. The reaction mixture was filtered and washed with
dichloromethane (10 mL). The filtrate was washed with water (12 mL) and brine (12 mL), and the
organic solution was separated, dried over anhydrous MgSO4 and concentrated under reduced pressure to
give dibromopyrazolone, which was recrystallized by dichloromethane/ether to afford 7 (0.42 g, 32%) as
pale yellow crystals. Rf=0.6 (5% methanol in dichloromethane); mp 130°C (EtOH:Et2O:hexane, 1:2:4,
1
v/v); (lit.,20 mp 132–133oC); IR (nujol, NaCl) 3350, 2923, 1721, 1377, 1286 cm-1; H NMR (CDCl3) δ
9.99 (br s, 1H), 2.27 (s, 3H); 13C NMR (CDCl3) δ 170.4, 156.4, 45.7, 13.6; HRMS Calcd for
C4H5N2OBr2: 254.8763 [M+H]+, Found: 254.8759.

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General Procedure for the Preparation of 4-Bromo-3-pyrazolin-5-one Derivatives (8a−b)
To a solution of pyrazolones (8.0 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (0.34 g,
8.4 mmol, 60%, washed with dry hexane). N-bromosuccinimide (1.50 g, 8.4 mmol) was added
portionwise to the suspension at 0oC under an argon atmosphere. The reaction mixture was stirred at rt for
3 h. The mixture was filtered and washed with dichloromethane (10 mL). The organic residue was
concentrated under reduced pressure to give bromo pyrazolone, which was purified by flash column
chromatography using eluent, 5% methanol in dichloromethane to afford white crystals.
4-Bromo-5-methyl-1,2-dihydro-3H-pyrazol-3-one (8a)
Yield; 78%; Rf=0.3 (5% methanol in dichloromethane); mp 191°C (EtOH:Et2O:hexane, 1:2:4, v/v); (lit.,21
1
192–194oC); IR (nujol, NaCl) 3366, 2924, 1614, 1461, 1171 cm-1; H NMR (DMSO−d6) δ 11.15 (br s,
13
2H), 2.07 (s, 3H); C NMR (DMSO−d6) δ 158.6, 138.8, 78.4, 11.2; MS (ESI) (m/z) 176 [M+H]+ (base
peak), 140, 99; 198 [M+Na]+.
4-Bromo-5-methyl-1-[4-methylphenylsulfonyl]-1,2-dihydro-3H-pyrazol-3-one (8b)
Yield; 86%; Rf=0.6 (5% methanol in dichloromethane); mp 103°C (EtOH:Et2O:hexane, 1:2:4, v/v); IR
(nujol, NaCl) 3176, 2942, 1594, 1377 cm-1; 1H NMR (CDCl3) δ 12.90 (br s, 1H), 7.79 (d, J=8.3 Hz, 2H),
7.46 (d, J=8.3 Hz, 2H), 2.49, (s, 3H), 2.14 (s, 3H); 13C NMR (CDCl3) δ 162.7, 151.7, 140.3, 133.1, 130.9,
129.2, 84.2, 22.0, 11.0; MS (ESI) (m/z) 330 [M+H]+, 293, 252 (base peak), 218; HRMS Calcd for
C11H12BrN2O3S: 330.9747 [M+H]+, Found: 330.9739.
General Procedure for the Preparation of Bicyclic Pyrazolone Compounds: Diels-Alder Reactions
To a stirred solution of 3-methyl-3-pyrazolin-5-one (4a, 0.98 g, 10.0 mmol) or 4-ethoxycarbonyl-3-
methylpyrazolin-5-one (4b, 1.70 g, 10.0 mmol) and 1,3-dienes (10.0 mmol) in dichloromethane (50 mL)
was added portionwise lead(IV) acetate (4.66 g, 10.5 mmol) at –10oC under an argon atmosphere. The
reaction mixture was stirred at rt for 3 h. The mixture was diluted with dichloromethane (20 mL) and
washed with 5% aq. sodium carbonate solution (20 mL), water (20 mL) and brine (20 mL). The organic
layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel using 3–10% methanol in dichloromethane to give
products.

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3,6-Dimethyl-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazin-1-one (10a)/3,7-dimethyl-5,8-dihydro-1H-
pyrazolo[1,2-a]pyridazin-1-one (11a)
Rf=0.5 (10% methanol in dichloromethane); mp 116°C (EtOH:Et2O:hexane, 1:2:4, v/v); IR (nujol, NaCl)
1
2927, 2853, 1700, 1686, 1258 cm-1; H NMR (CDCl3) δ 5.04 (d, J=19.3 Hz, 1H), 4.59 (s, 1H), 3.45 (s,
13
2H), 3.37 (s, 2H), 1.56 (s, 3H), 1.22 (s, 3H); C NMR (CDCl3) δ 165.8, 151.2, 127.9, 114.5, 95.8, 48.7,
42.9, 19.8, 11.5; MS (ESI) (m/z) 165 [M+H]+, (base peak), 142; 187 [M+Na]+.
5-Methoxy-3-methyl-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazin-1-one (10b)/8-methoxy-3-methyl-5,8-
dihydro-1H-pyrazolo[1,2-a]pyridazin-1-one (11b)
1
Rf=0.3 (3% methanol in dichloromethane); oil; IR (nujol, NaCl) 2933, 1644, 1417, 1076 cm-1; H NMR
(CDCl3) δ 6.04 (s, 2H), 5.75 (s, 1H), 5.35 (s, 1H), 4.23 (d, J=15.8 Hz, 1H), 3.70 (d, J=16.0 Hz, 1H), 3.43
(s, 3H), 2.13 (s, 3H); 13C NMR (CDCl3) δ 167.1, 155.9, 124.5, 123.5, 120.6, 99.4, 57.3, 46.6, 12.5;
HRMS Calcd for C9H13N2O2: 181.0972 [M+H]+, Found: 181.0973.
3,6,7-Trimethyl-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazin-1-one (10c)
Rf=0.4 (4% methanol in dichloromethane); mp 51–52°C [purified by FC (CH2Cl2:MeOH, 96:4, v/v)]; IR
1
(nujol, NaCl) 2918, 1602, 1291, 1150 cm-1; H NMR (CDCl3) δ 5.24 (s, 1H), 4.02 (s, 2H), 3.81 (s, 2H),
13
2.11 (s, 3H), 1.71 (s, 6H); C NMR (CDCl3) δ 166.4, 151.4, 121.6, 119.6, 97.3, 49.3, 45.7, 16.4, 16.2,
12.3; HRMS Calcd for C10H15N2O: 179.1179 [M+H]+, Found: 179.1176.
3,5,5,8,8-Pentamethyl-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazin-1-one (10d)
1
Rf=0.5 (5% methanol in dichloromethane); oil; IR (nujol, NaCl) 2976, 1675, 1569, 1142 cm-1; H NMR
(CDCl3) δ 5.35 (d, J=5.8 Hz, 1H), 5.32 (d, J=5.8 Hz, 1H), 5.05 (s, 1H), 2.18 (s, 3H), 1.83 (s, 3H), 1.77 (s,
13
3H), 1.49 (s, 3H), 1.17 (s, 3H); C NMR (CDCl3) δ 162.7, 157.8, 154.5, 142.9, 117.7, 93.2, 63.6, 26.6,
24.5, 21.4, 19.0, 15.6; HRMS Calcd for C12H19N2O: 207.1492 [M+H]+, Found: 207.1520.
5,8-Diphenyl-3-methyl-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazin-1-one (10e)
Rf=0.5 (5% methanol in dichloromethane); mp 166–167°C (CH2Cl2:Et2O:hexane, 1:2:6, v/v); IR (nujol,
NaCl) 2924, 1663, 1645, 1151 cm-1; 1H NMR (CDCl3) δ 7.36−7.26 (m, 10H), 6.08 (dq, J=2.0, J=2.2 Hz,
13
1H), 5.90 (br s, 1H), 5.80 (d, J=10.1 Hz, 1H), 5.36 (br s, 1H), 5.14 (d, J=2.1 Hz, 1H), 1.72 (s, 3H); C
NMR (CDCl3) δ 165.4, 155.0, 139.8, 129.8, 129.1, 128.2, 127.4, 126.4, 124.0, 100.5, 62.1, 54.8, 14.7;
HRMS Calcd for C20H19N2O: 303.1492 [M+H]+, Found: 303.1493.

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6,7-Dibenzyl-3-methyl-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazine-1-one (10f)
1
Rf=0.5 (5% methanol in dichloromethane); oil; IR (nujol, NaCl) 3059, 2848, 1642, 1453, 1269 cm-1; H
NMR (CDCl3) δ 7.35−7.19 (m, 10H), 5.27 (s, 1H), 4.15 (s, 2H), 3.86 (s, 2H), 3.69 (s, 2H), 3.67 (s, 2H),
13
2.05 (s, 3H); C NMR (CDCl3) δ 166.7, 162.7, 152.2, 138.1, 129.3, 129.2, 128.9, 128.7, 127.3, 127.2,
124.6, 98.1, 48.0, 44.6, 36.9, 36.7, 12.3; HRMS Calcd for C22H23N2O: 331.1805 [M+H]+, Found:
331.1808.
Ethyl 3,7-dimethyl-1-oxo-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazin-2-carboxylate (10g)/ethyl 3,6-
dimethyl-1-oxo-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazine-2-carboxylate (11g)
Rf=0.6 (10% methanol in dichloromethane); mp 118°C [purified by FC (CH2Cl2:MeOH, 96:4, v/v)]; IR
(nujol, NaCl) 2924, 1701, 1637, 1459, 1178 cm-1; 1H NMR (CDCl3) δ 5.68 (d, J=23.6 Hz, 1H), 4.32 (d,
J=14.9 Hz, 2H), 4.09 (q, J=7.1 HZ, 2H), 3.97 (d, J=17.5 Hz, 2H), 2.42 (s, 3H), 1.79 (s, 3H), 1.19 (t, J=7.1
13
Hz, 3H); C NMR (CDCl3) δ 164.1, 162.9, 153.6, 128.0, 114.7, 96.7, 59.4, 46.6, 43.4, 20.5, 15.3, 12.1;
MS (ESI) (m/z) 237 [M+H]+, (base peak), 191, 82; 259 [M+Na]+; HRMS Calcd for C12H17N2O3:
237.1234 [M+H]+, Found: 237.1228.
Ethyl 8-acetyloxy-3-methyl-1-oxo-7,8-dihydro-1H-pyrazolo[1,2-a]pyridazin-2-carboxylate (10h)
ethyl 5-acetyloxy-3-methyl-1-oxo-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazine-2-carboxylate (11h)
Rf=0.5 (5% methanol in dichloromethane); semisolid; IR (nujol, NaCl) 2935, 1714, 1696, 1633, 1150
cm-1; 1H NMR (CDCl3) δ 6.89 (s, 1H), 6.14 (s, 2H), 4.29−4.20 (m, 4H), 2.55 (s, 3H), 1.98 (s, 3H), 1.33 (t,
13
3H, J=7.03); C NMR (CDCl3) δ 167.0, 163.9, 162.7, 158.8, 124.6, 121.5, 99.8, 71.2, 60.5, 45.2, 21.1,
14.8, 12.3; HRMS Calcd for C13H17N2O5: 281.1132 [M+H]+, Found: 281.1133.
Ethyl 3,6,7-trimethyl-1-oxo-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazine-2-carboxylate (10i)
Rf=0.4 (5% methanol in dichloromethane); mp 187–188°C (EtOH:Et2O, 1:10, v/v); IR (nujol, NaCl) 2924,
1715, 1619, 1140 cm-1; 1H NMR (CDCl3) δ 4.27 (q, J=7.1 Hz, 2H), 4.08 (br s, 4H), 2.50 (s, 3H), 1.76 (s,
6H), 1.33 (t, J=7.1 Hz, 3H); 13C NMR (CDCl3) δ 164.5, 164.1, 152.4, 121.4, 118.4, 98.6, 60.2, 48.1, 46.0,
16.4, 16.3, 14.9, 11.9; HRMS Calcd for C13H19N2O3: 251.1390 [M+H]+, Found: 251.1392. Anal. Calcd
for C, 62.38; H, 7.25; N, 11.19. Found: C, 62.17; H, 7.28; N, 11.12.
Ethyl 3,5,5,8,8-pentamethyl-1-oxo-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazine-2-carboxylate (10j)
Rf=0.5 (5% methanol in dichloromethane); mp 78°C (CH2Cl2:Et2O:hexane, 1:2:6, v/v); IR (nujol, NaCl)
2926, 1705, 1570, 1134 cm-1; 1H NMR (CDCl3) δ 5.48 (d, J=7.2 Hz, 1H), 5.42 (d, J=7.2 Hz, 1H), 4.21 (q,

HETEROCYCLES, Vol. 65, No. 1, 2005
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J=6.9 Hz, 2H), 2.39 (s, 3H), 1.84 (s, 3H), 1.78 (s, 3H), 1.53 (s, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.22 (s, 3H);
13C NMR (CDCl3) δ 163.4, 162.7, 158.6, 156.1, 143.7, 117.0, 94.8, 64.0, 60.0, 26.6, 24.6, 21.7, 19.1, 15.7,
14.9; HRMS Calcd for C15H23N2O3: 279.1703 [M+H]+, Found: 279.1688. Anal. Calcd for C, 64.73; H,
7.97; N, 10.06. Found: C, 64.74; H, 8.20; N, 10.06.
Ethyl 3-methyl-1-oxo-5,8-diphenyl-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazine-2-carboxylate (10k)
Rf=0.4 (5% methanol in dichloromethane); mp 186–187°C (MeOH:Et2O:hexane, 1:2:4, v/v); IR (nujol,
1
NaCl) 2924, 1715, 1637, 1104 cm-1; H NMR (CDCl3) δ 7.32−7.18 (m, 10H), 5.99 (br s, 2H), 5.66 (d,
J=15.7 Hz, 2H), 4.24 (q, J=7.1 Hz, 2H), 2.27 (s, 3H), 1.28 (t, J=7.1 Hz, 3H); 13C NMR (CDCl3) δ 164.6,
163.0, 154.5, 138.7, 129.9, 129.1, 128.4, 128.0, 126.1, 124.4, 123.9, 99.5, 60.3, 59.3, 56.8, 14.9, 12.8;
HRMS Calcd for C23H23N2O3: 375.1703 [M+H]+, Found: 375.1704. Anal. Calcd for C, 73.78; H, 5.92; N,
7.48. Found: C, 73.85; H, 5.85; N, 7.42.
Ethyl 6,7-dibenzyl-3-methyl-1-oxo-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazine-2-carboxylate (10l)
Rf=0.5 (5% methanol in dichloromethane); mp 149–150°C (MeOH:Et2O:hexane, 1:2:4, v/v); IR (nujol,
1
NaCl) 3061, 2923, 1700, 1627, 1147 cm-1; H NMR (CDCl3) δ 7.33−7.15 (m, 10H), 4.27 (q, J=7.1 Hz,
13
2H), 4.19 (s, 2H), 4.11 (s, 2H), 3.70 (s, 4H), 2.49 (s, 3H), 1.33 (t, J=7.1 Hz, 3H); C NMR (CDCl3) δ
164.4, 163.3, 162.7, 153.0, 137.8, 137.6, 129.4, 129.2, 128.8, 128.7, 127.5, 127.3, 127.0, 123.6, 99.0, 60.2,
46.8, 44.9, 36.9, 36.7, 14.8, 11.9; HRMS Calcd for C25H27N2O3: 403.2016 [M+H]+, Found: 403.2030.
Anal. Calcd for C, 74.60; H, 6.51; N, 6.96. Found: C, 74.36; H, 6.44; N, 6.93.
Diethyl 3,5-dimethyl-1,7-dioxo-1H, 7H-pyrazolo[1,2-a]pyrazole-2,6-dicarboxylate (13)/diethyl 3,7-
dimethyl-1,5-dioxo-1H, 5H-pyrazolo[1,2-a]pyrazole-2,6-dicarboxylate (14)
To a stirred solution of 4-ethoxycarbonyl-3-methylpyrazolin-5-one (0.34 g, 2.0 mmol) in
dichloromethane (40 mL) was added portionwise lead(IV) acetate (0.98 g, 2.2 mmol) at 0oC under an
argon atmosphere. The reaction mixture was stirred at rt for 6 h. The mixture was diluted with
dichloromethane (20 mL) and washed with 5% aq. sodium carbonate solution (20 mL), water (15 mL)
and brine (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by column chromatography on silica gel using 5%
methanol in dichloromethane to afford 13 (74 mg, 12%) and 14 (74 mg, 12%), respectively. Compound
(13); Rf=0.3 (5% methanol in dichloromethane); mp 259 oC (Et2O); IR (nujol, NaCl) 2922, 2854, 1772,
1
1702, 1461, 1377 cm-1; H NMR (DMSO−d6) δ 4.25 (q, J=7.1 Hz, 2H), 2.80 (s, 3H), 1.27 (t, J=7.1 Hz,
13
3H); C NMR (DMSO−d6) δ 161.4, 156.1, 154.4, 108.2, 60.8, 14.4, 13.3; MS (ESI) (m/z) 309 [M+H]+,

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HETEROCYCLES, Vol. 65, No. 1, 2005
(base peak), 256, 143; HRMS Calcd for C14H17N2O6: 309.1081 [M+H]+, Found: 309.1087. Anal. Calcd
for C14H17N2O6: C, 54.54; H, 5.23; N, 9.09. Found: C, 54.62; H, 5.16; N, 8.94. Compound (14); Rf=0.4
(5% methanol in dichloromethane); mp 171°C (Et2O); IR (nujol, NaCl) 2923, 2853, 1746, 1695, 1462,
1366 cm-1; 1H NMR (DMSO−d6) δ 4.33 (q, J=7.1 Hz, 2H), 2.91 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); 13C NMR
(DMSO−d6) δ 161.7, 157.7, 156.0, 107.1, 61.5, 14.6, 12.7; MS (ESI) (m/z) 309 [M+H]+, (base peak), 269,
143; HRMS Calcd for C14H17N2O6: 309.1081 [M+H]+, Found: 309.1073. Anal. Calcd for C, 54.54; H,
5.23; N, 9.09. Found: C, 54.54; H, 5.18; N, 8.98.
3-Methyl-1H-pyrazolo[1,2-a]pyridazin-1-one (15)
To a stirred solution of pyridazins (10b or 11b, 0.5 g, 2.8 mmol) in methanol (12 mL) potassium
carbonate (2.2 g, 16.8 mmol) was added and the reaction mixture was refluxed for 2 h. The mixture was
cooled to rt and diluted with dichloromethane (10 mL) and filtered through a pad of celite 545 and then
concentrated under reduced pressure. The residue was purified by flash column chromatography to give
pale yellow solid (66 mg, 16%). Rf=0.3 (5% methanol in dichloromethane); mp 113−114 oC (Et2O:hexane,
10:1, v/v); (lit.,18 115−117 oC ); IR (nujol, NaCl) 3059, 2848, 1642, 1453, 1269 cm-1; 1H NMR (CDCl3) δ
7.50 (d, J=7.5 Hz, 1H), 7.01 (d, J=7.0 Hz, 1H), 5.77 (dd, J=6.0, 7.0 Hz, 1H), 5.74 (dd, J=6.5, 6.0 Hz, 1H),
5.56 (s, 1H), 2.30 (s, 3H); 13C NMR (CDCl3) δ 155.9, 134.7, 121.9, 120.8, 106.0, 103.4, 94.3, 11.2;
HRMS Calcd for C8H9N2O: 149.0710 [M+H]+, Found: 149.0710.
7-Methoxy-3-methyl-7,8-dihydro-1H-pyrazolo[1,2-a]pyridazin-1-one (16a)/6-methoxy-3-methyl-5,6-
dihydro-1H-pyrazolo[1,2-a]pyridazin-1-one (16b) Yield: 42%; Rf=0.4 (5% methanol in
1
dichloromethane); pale yellow oil; IR (nujol, NaCl) 2940, 1645, 1431, 1308, 1085 cm-1; H NMR
(CDCl3) δ 6.58 (dd, J=2.0, 8.2 Hz, 1H), 5.70 (d, J=3.6 Hz, 1H), 5.23 (s, 1H), 5.16−5.01 (m, 1H), 3.31 (s,
13
3H), 2.54−2.50 (m, 2H), 2.20 (s, 3H); C NMR (CDCl3) δ 161.2, 148.9, 118.5, 100.0, 97.3, 80.9, 55.8,
28.6, 11.7; GC-MS 181 [M+H]+, 149 (base peak), 122, 81, 54; HRMS Calcd for C9H12N2O2Na: 203.0796
[M+ Na]+, Found: 203.0800.
ACKNOWLEDGEMENTS
This project was supported by a Grant/Cooperative Agreement (UR3/CCU418652) from the Centers for
Disease Control and Prevention (CDC). We would also like to thank Frank T. Wiggers for NMR
spectroscopy and Dr. Chuck Dunbar for the mass spectral data.

HETEROCYCLES, Vol. 65, No. 1, 2005
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