A simple approach to pyrazol-3-ones via diazenes

Article abstract of DOI:10.1016/j.tet.2009.08.047

An efficient entry into pyrazol-3-ones is described starting from propenoic acids that were first transformed into the corresponding hydrazides. Oxidation of the hydrazides gave the diazenes and the latter cyclized to pyrazol-3-ones on treatment with ZrCl₄. The methoxycarbonyl protection of the N-1 of the pyrazolone derivatives was easily removed under mild reaction conditions.

Full text of DOI:10.1016/j.tet.2009.08.047

Tetrahedron 65 (2009) 8690–8696
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A simple approach to pyrazol-3-ones via diazenes
*
ˇ
Bojan Burja, Marijan Kocevar, Slovenko Polanc
ˇ
ˇ
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, SI-1000 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 June 2009
Received in revised form 11 August 2009
Accepted 20 August 2009
Available online 25 August 2009
An efficient entry into pyrazol-3-ones is described starting from propenoic acids that were first trans-
formed into the corresponding hydrazides. Oxidation of the hydrazides gave the diazenes and the latter
cyclized to pyrazol-3-ones on treatment with ZrCl4. The methoxycarbonyl protection of the N-1 of the
pyrazolone derivatives was easily removed under mild reaction conditions.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Diazenes
Intramolecular amination
Pyrazol-3-ones
Mild hydrolysis
1. Introduction
appropriate C3 synthon with hydrazine or its derivative, which
leads to the formation of the C3–N2 bond of the pyrazole ring in the
The pyrazole moiety1 is present in a plethora of natural and
synthetic compounds.2 It is involved in a number of biologically
active molecules3 and can act as an efficient coordinating ligand.4
Pyrazol-3-ones are typical representatives of the pyrazole de-
rivatives. Their syntheses, reactivity, and numerous applications are
well documented.5 They belong to a broad family of compounds
that serve as products and intermediates in analytical, agricultural,
biological, and pharmaceutical chemistry. Some of them are used as
important pharmaceutical agents (antipyrine and its congeners).6
Recently, 4,5-diaryl-1H-pyrazole-3-ol was utilized as a versatile
template for synthesizing the compounds that act as potential
cyclooxygenase-2 (COX-2) inhibitors and also show good selectivity
for COX-2 versus COX-1 enzymes.7 Some pyrazolones showed in-
final step. Examples of an alternative option, i.e., C5–N1 ring-clo-
sure, are rare and are limited by the pool of starting materials.5a A
recent paper by Prata et al. describes the cyclization of 3-arylpro-
panoylhydrazides leading to the mixtures of the corresponding
1-azaspiro[4.5]deca-6,9-diene-2,8-diones and 3,4-dihydroquinolin-
2(1H)-ones.11 They also report on two experiments involving 3-
arylpropenoylhydrazides that gave another type of products
(Scheme 1). Thus, the oxidation of 4-fluorocinnamic hydrazide 1a
with (diacetoxyiodo)benzene, followed by the treatment with
BF3$Et2O resulted in rather poor yield (23%) of the pyrazol-3-one
2a. The same reaction sequence starting from cinnamic hydrazide
1b gave the mixture of pyrazol-3-ones 2b and 3b in 45% and 9%
O
H
hibition of TNF-a production in response to the tumor promotor
TPA on HL-60 cells.8 Denis et al. very recently reported on the
synthesis and biological activity of new pyrazol-3-ones.9 They
found that these compounds effectively inhibited heptosyl-
transferase WaaC, which represents an attractive target for the
discovery of new Gram-negative antibacterial drugs based on an
antivirulence mechanism. In addition, pyrazolone derivatives were
demonstrated as inhibitors of the accumulation of the abnormal
protease-resistant form of prion protein (PrP-res).10
N
N
CO Me
2
H
R
1a R = F
1b R = H
1. PhI(OAc)2
.
2. BF3 Et2O
CO Me
2
In the light of the above-mentioned properties, there is a per-
manent need for new approaches toward pyrazol-3-ones. Usually,
the synthesis of pyrazol-3-ones relies on the reaction of the
CO Me
2
N
R
NH
N
+
NH
O
O
2a R = F
3b
2b R = H
* Corresponding author. Tel.: þ386 1 24 19 236; fax: þ386 1 24 19 271.
E-mail address: slovenko.polanc@fkkt.uni-lj.si (S. Polanc).
Scheme 1.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.047

B. Burja et al. / Tetrahedron 65 (2009) 8690–8696
8691
yields, respectively. The reason for the poor yield of pyrazol-3-one
2a in the first case and the mixture of products in the second ex-
periment seemed to be an unsuitable choice of reagents employed
in the procedure. In order to check this hypothesis and to improve
the outcome of the reaction sequence we first performed on the
same substrates the oxidation with NBS, followed by the cyclization
in the presence of ZrCl4. Our results were indeed essentially better:
(i) the pyrazol-3-one 2a was isolated in 91% yield; (ii) the cycliza-
tion of 1b led to 2b in 65% yield accompanied by only 3% of 3b.
multistep approach starting from simple compounds is outlined in
Scheme 3. Thus, easily available propenoic acids 6 reacted with
oxalyl chloride in the presence of catalytic amounts of DMF to give
the acid chlorides 7. The latter were not isolated but were imme-
diately exposed to methyl carbazate to obtain the hydrazides 8.
Oxidation of the NHNH moiety in 8 was conducted with NBS using
pyridine as a base to yield the diazenes 4 that usually appeared as
red, oily products.
O
O
(COCl)2
2. Results and discussion
DMF (cat)
R1
OH
R1
Cl
CH2Cl2
Based on our previous experiences with diazenes12 we became
interested in intramolecular cyclizations of 3-substituted prope-
noyldiazenecarboxylates, which can be considered as the dehydro-
analogues of the hydrazides 1. For the initial studies concerning the
ring-closure reactions we selected the diazene 4a (Scheme 2),
having three donating groups at the benzene ring but otherwise
related to the diazenes that are probably formed from 1 on oxida-
tion. To perform the cyclization of 4a we chose ZrCl4 as a Lewis acid
because its catalytic power has already been proven in various
electrophilic aminations.13 Although it is impossible to a priori
exclude another reaction that would eventually lead to the different
product, we isolated the pyrazol-3-one 5a as the sole product in
a high yield (Scheme 2). The exclusive formation of the product 5a
may be explained by the initial attack of the ZrCl4 at the carbonyl
oxygen to give the dipolar species I, which serves as an internal
nitrogen electrophile yielding the product 5a upon cyclization. We
have already demonstrated the use of ZrCl4 for intramolecular
electrophilic aminations of diazenes, i.e., arylaminocarbonyldiaze-
nedicarboxylates that led to the formation of the 2-imidazolone
ring as a consequence of the Lewis acid’s attack at the ester car-
bonyl oxygen.13a It seems that the site of the ZrCl4 binding regulates
the outcome of the process.
R2
R2
0 °C to rt
−
1.5 5 h
7
6
H2NNHCO2Me
CH2Cl2, Py
0 °C to rt
−
15 23 h
O
O
H
N
N
NBS, Py
rt
R1
N
CO2Me
R1
N
H
CO2Me
R2
R2
−
5 35 min
8
4
a: R1 = 3,4,5-tri-MeO-C6H2; R2 = H
: R1 = 2,3-di-MeO-C6H3; R2 = H
b
: R1 = 4-AcO-C6H4; R2 = H
ZrCl4
CH2Cl2
rt, 1 4.5 h
c
d: R1 = 3-MeO-,4-AcO-C6H3; R2 = H
e: R1 = 3,4-di-AcO-C6H3; R2 = H
−
: R1 = 2-thienyl; R2 = H
f
: R1 = 3-thienyl; R2 = H
g
h: R1 = 4-NO2-C6H4; R2 = H
i: R1 = 4-Cl-C6H4; R2 = H
CO2Me
N
: R1 = 4-F-C6H4; R2 = H
R1
R2
j
NH
: R1 = Ph; R2 = H
k
l: R1 = Ph; R2 = Me
m: R1 = R2 = Ph
O
O
9
MeO
MeO
N
N
CO2Me
Scheme 3.
4a
OMe
Although the diazenes 4 were generally not isolated, as they
were quite unstable, we did succeed in the purification and char-
acterization of the diazene 4d. The last step of the above sequence
that involved the treatment of the diazenes 4 with ZrCl4 at room
temperature gave the pyrazol-3-ones 9 in good-to-excellent yield
(Table 1).
ZrCl4
CH2Cl2
rt
ZrCl4
O
Table 1
MeO
MeO
N
Pyrazol-3-ones prepared from propenoic acids 6 via their hydrazides
N
CO2Me
Entry Propenoic acid Hydrazide Yielda (%) Pyrazol-3-one Yielda (%)
I
1
6a
6b
6c
6d
6e
6f
8a
8b
8c
8d
8e
8f
94
94
98
88
91
98
97
93
99
88
95
96
99
9a
9b
9c
9d
9e
9f
97
97
76
95
76
89
90
77
86
91
64b
92
96
OMe
MeO
2
3
4
5
6
7
8
9
6g
6h
6i
8g
8h
8i
9g
9h
9i
CO2Me
MeO
N
NH
10
11
12
13
6j
6k
6l
1a
1b
8l
2a
2b
9l
MeO
5a
Scheme 2.
O
6m
8m
9m
a
Yields of isolated products are given.
After chromatographic separation from 4-phenyl isomer 3b (3%).
b
Encouraged by the above-mentioned result we focused our
attention on the scope of this ring-closure with regard to the
synthesis of various pyrazol-3-ones. Initial experiments confirmed
that the cyclization can serve as the final step in a general route
to 1-methoxycarbonyl-5-aryl substituted pyrazol-3-ones. This
Most of the products (entries 1–11) are representatives of the
pyrazole derivatives that are unsubstituted at the position 4. As
demonstrated by the conversion of 6l and 6m into 9l and 9m

8692
B. Burja et al. / Tetrahedron 65 (2009) 8690–8696
(entries 12 and 13) this approach works equally well if 2,3-di-
substituted propenoic acids are applied as the starting materials
and give the corresponding 4,5-disubstituted pyrazol-3-ones 9l
and 9m.
4. Experimental
4.1. General methods
The methoxycarbonyl functionality in the product 9 can be
considered as an N-1 protecting group. It seemed reasonable to
perform the hydrolysis of the pyrazol-3-ones 9 as well as 2a and 2b.
The application of trimethylsilyl iodide is well documented14 and
was the first method we selected for this purpose. Although the
reaction of pyrazol-3-ones with trimethylsilyl iodide in methylene
chloride led to the deprotection of the N-1 under microwaves in
a moderate yield (a 53% yield starting from 9l) we also checked an
elegant method recently described by Theodorou et al.15 Namely,
they developed a mild and efficient procedure for the alkaline hy-
drolysis of esters under non-aqueous conditions that also worked
well in our case (Table 2). Thus, pyrazol-3-ones were treated with
a methanolic solution of NaOH in the mixture CH2Cl2/MeOH at
room temperature for 1–4 h. The resulting mixture was evaporated
to dryness and the residue acidified with aqueous HCl to give, via
the unstable acids 10, the final products 11. This process is ac-
companied by the hydrolysis of the acetoxy functionality when the
latter is attached to the benzene ring giving a free phenolic OH
group (Table 2, entries 3–5).
Solvents and starting compounds were obtained from com-
mercial sources (Fluka, Sigma, and Aldrich). TLC was carried out on
Fluka silica-gel TLC-cards. All mps were determined on a hot stage
apparatus and are uncorrected. IR spectra were recorded on a Bio-
Rad FTS 3000MX instrument. NMR spectra were recorded on
a Bruker Avance 300 DPX spectrometer at 302 K. Chemical shifts
are reported in
d
ppm, referenced to an internal TMS standard for
1H NMR, DMSO-d6
(
d
39.5) for 13C NMR. Microanalyses were per-
formed on a Perkin–Elmer 2400 series II CHNS/O analyser. Mass
spectra and high-resolution mass measurements were performed
on a VG-Analytical Autospec EQ instrument.
4.2. General procedure for the synthesis of hydrazides 8
Oxalyl chloride (15.543 g, 120 mmol) was slowly added to
a
stirred mixture of the acid 6 (60 mmol) and N,N-dime-
thylformamide (2–3 drops) in dry CH2Cl2 (90 mL) at 0 ꢀC under
argon. The reaction mixture was stirred at room temperature for an
additional 2–5 h and evaporated to dryness to give the corre-
sponding acid chloride 7 in a quantitative yield. Then, a solution of
7 in dry CH2Cl2 (100 mL) was slowly added to a stirred solution of
methyl carbazate (5.515 g, 60 mmol) and pyridine (4.986 mL,
62.4 mmol) in dry CH2Cl2 (100 mL) at 0 ꢀC. The reaction mixture
was then stirred at room temperature for 15–23 h, water was added
(50 mL), the mixture was left at room temperature for 3 h, and the
solid material (8) was filtered off. If no precipitation occurred, the
organic phase was separated, dried over anhydrous sodium sulfate,
and evaporated to dryness to give the hydrazide 8 in an excellent
yield.
Table 2
Hydrolysis of 1-methoxycarbonyl substituted pyrazol-3-ones
1. NaOH/MeOH
CH2Cl2/MeOH
CO2Me
CO2H
H
N
R1
R2
N
R1
R2
R1
R2
N
−
rt, 1 4.5 h
−
NH
CO2
NH
NH
O
2. HCl
O
O
9
10
11
Entry
Starting material
Product
Yielda (%)
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
9g
9h
9i
11a
11b
11cb
11dc
11ed
11f5b
11g
11h
11i
80
94
97
97
99
97
80
82
96
89
93
83
99
4.2.1. Methyl 2-[(2E)-3-(3,4,5-trimethoxyphenyl)prop-2-enoyl]hydra-
zinecarboxylate (8a). Reaction time: 2 h (for 7a) and 18 h. White
needles; mp 82.1–84.6 ꢀC (MeOH). IR (KBr): 3496, 3302, 1728,
1618, 1586, 1277, 1235, 1126. 1H NMR (DMSO-d6):
d 3.63 (s, 3H),
3.71 (s, 3H), 3.84 (s, 6H), 6.60 (d, J¼15.9 Hz, 1H), 6.95 (s, 2H),
7.51 (d, J¼15.9 Hz, 1H), 9.19 (br s, 1H), 9.83 (br s, 1H). 13C NMR
9
10
11
12
13
2a
2b
9l
11j
11k
11l
(DMSO-d6):
d 52.0, 56.0, 60.1, 105.3, 118.7, 130.2, 139.1, 140.6,
153.2, 156.7, 165.0. MS (EI) m/z (%) 310 (Mþ, 34), 221 (100), 190
(35), 163 (21). HRMS calcd for C14H18N2O6 (Mþ): 310.1165.
Found: 310.1170.
9m
11m
a
Yields of isolated products are given.
R1¼4-HO–C6H4.
b
c
4.2.2. Methyl 2-[(2E)-3-(2,3-dimethoxyphenyl)prop-2-enoyl]hydrazine-
carboxylate (8b). Reaction time: 3 h (to obtain 7b) and 20 h (trans-
formation of 7b into 8b). White needles; mp 133.0–134.0 ꢀC
(EtOAc). IR (KBr): 3464, 3275, 1724, 1655, 1620, 1481, 1274, 1229. 1H
R1¼3-MeO–, 4-HO–C6H3.
R1¼3,4-di-HO–C6H3.
d
3. Conclusions
NMR (DMSO-d6):
J¼15.9 Hz, 1H), 7.15 (m, 3H), 7.76 (d, J¼15.9 Hz, 1H), 9.21 (br s, 1H),
9.96 (br s, 1H). 13C NMR (DMSO-d6):
52.0, 55.8, 60.7, 114.2, 118.8,
120.6, 124.4, 128.1, 134.9, 147.6, 152.9, 156.7, 165.0. MS (EI) m/z (%)
280 (Mþ, 5), 191 (100), 176 (38), 148 (12). Anal. Calcd for C13H16N2O5
(280.28): C, 55.71; H, 5.75; N, 9.99. Found: C, 55.91; H, 5.93; N,
10.05.
d 3.64 (s, 3H), 3.78 (s, 3H), 3.84 (s, 3H), 6.69 (d,
In conclusion, we have described an efficient entry into pyra-
zolones, applying commercially available propenoic acids as the
starting materials. This is a simple method for constructing of the
pyrazole ring by forming the N1–C5 bond. The diazenes formed by
the oxidation of the corresponding hydrazides do not need to be
isolated and cyclize in the presence of ZrCl4 to the desired pyrazol-
3-ones. As far as we know, there are no reports in the literature
concerning a general route to pyrazol-3-ones via a regioselective
ring-closure of the diazenes. This simple and straightforward
method is useful for the preparation of various N-1 protected pyr-
azol-3-ones. The protecting group, i.e., methoxycarbonyl, can be
easily removed under mild reaction conditions, which enables
further modifications of the pyrazolone molecule. The mild re-
action conditions applied in the all steps, the simple procedures,
the relatively rapid conversions, and the good-to-excellent yields
are all notable characteristics of this protocol.
d
4.2.3. Methyl 2-[(2E)-3-(4-acetoxyphenyl)prop-2-enoyl]hydrazine-
carboxylate (8c). Reaction time: 3 h 30 min (for 7c) and 21 h. White
needles; mp 166.8–168.5 ꢀC (EtOAc). IR (KBr): 3326, 1751, 1660,
1625, 1489, 1214, 1199, 1166. 1H NMR (DMSO-d6):
d 2.29 (s, 3H), 3.65
(s, 3H), 6.65 (d, J¼15.9 Hz, 1H), 7.21 and 7.68 (AA0XX0, J¼8.7 Hz, 4H),
7.60 (d, J¼15.9 Hz, 1H), 9.24 (br s, 1H), 9.97 (br s, 1H). 13C NMR
(DMSO-d6): d 20.8, 52.0, 119.4,122.5, 129.0, 132.3,139.6, 151.6, 156.8,
164.9, 169.1. MS (EI) m/z (%) 278 (Mþ, 1), 189 (51), 147 (100), 69 (41).
Anal. Calcd for C13H14N2O5 (278.26): C, 56.11; H, 5.07; N, 10.07.

B. Burja et al. / Tetrahedron 65 (2009) 8690–8696
8693
Found: C, 56.25; H, 5.26; N, 9.75. HRMS calcd for C13H14N2O5 (Mþ):
278.0903. Found: 278.0908.
m/z (%) 277.0 (MþNa)þ. Anal. Calcd for C11H11ClN2O3 (254.67): C,
51.88; H, 4.35; N, 11.00. Found: C, 51.96; H, 4.15; N, 11.04.
4.2.4. Methyl 2-[(2E)-3-(4-acetoxy-3-methoxyphenyl)prop-2-enoyl]-
hydrazinecarboxylate (8d). Reaction time: 5 h (for 7d) and 23 h.
White needles; mp 178.8–180.5 ꢀC (CH2Cl2). IR (KBr): 1765, 1717,
4.2.10. Methyl 2-[(2E)-(2-methyl-3-phenyl)prop-2-enoyl]hydrazinecar-
boxylate (8l). Reaction time: 4 h 30 min (for 7l) and 19 h 30 min.
White cubes; mp 115.4–117.3 ꢀC (EtOAc). IR (KBr): 3347, 3290, 1713,
1669,1631,1517,1264,1231,1198. 1H NMR (DMSO-d6):
d
2.27 (s, 3H),
1659, 1524, 1508, 1290, 1266. 1H NMR (DMSO-d6):
d
2.05 (s, 3H),
3.62 (s, 3H), 3.83 (s, 3H), 6.63 (d, J¼15.9 Hz, 1H), 7.14 (d, J¼8.4 Hz,
1H), 7.22 (dd, J1¼8.4 Hz, J2¼1.5 Hz, 1H), 7.37 (d, J¼1.5 Hz, 1H), 7.54
(d, J¼15.9 Hz, 1H), 9.19 (br s, 1H), 9.89 (br s, 1H). 13C NMR (DMSO-
3.64 (s, 3H), 7.38 (m, 6H), 9.12 (br s, 1H), 9.93 (br s, 1H). 13C NMR
(DMSO-d6): d 14.2, 51.9, 128.0, 128.5, 129.3, 130.6, 133.5, 135.7, 156.9,
168.8. MS (EI) m/z (%) 234 (Mþ, 2), 145 (100), 117 (79), 91 (29). Anal.
Calcd for C12H14N2O3 (234.25): C, 61.53; H, 6.02; N, 11.96. Found: C,
61.29; H, 6.19; N, 12.10.
d6):
d 20.4, 51.9, 55.8, 111.9, 119.6, 120.2, 123.3, 133.5, 139.8, 140.4,
151.1, 156.6, 164.7, 168.4. MS (EI) m/z (%) 308 (Mþ, 4), 219 (45), 177
(100), 145 (26). Anal. Calcd for C14H16N2O6 (308.29): C, 54.54; H,
5.23; N, 9.09. Found: C, 54.73; H, 5.19; N, 8.79. HRMS calcd for
C14H16N2O6 (Mþ): 308.1008. Found: 308.1015.
4.2.11. Methyl 2-[(2E)-(2,3-diphenyl)prop-2-enoyl]hydrazinecarboxy-
late (8m). Reaction time: 2 h (for 7m) and 20 h. White platelets; mp
147.6–148.9 ꢀC (EtOAc/heptane). IR (KBr): 3290, 3216, 1741, 1655,
4.2.5. Methyl 2-[(2E)-3-(3,4-diacetoxyphenyl)prop-2-enoyl]hydrazine-
carboxylate (8e). Reaction time: 3 h (for 7e) and 15 h. White nee-
dles; mp 181.4–183.9 ꢀC (MeOH). IR (KBr): 3309, 3214, 1766, 1737,
1610, 1501, 1248, 1217. 1H NMR (DMSO-d6):
d
3.62 (s, 3H), 7.04
(m, 2H), 7.19 (m, 5H), 7.36 (m, 4H), 9.17 (br s, 1H), 9.72 (br s, 1H). 13C
NMR (DMSO-d6): d 51.9, 128.0, 128.2, 128.4, 128.7, 129.4, 129.6, 134.0,
1622, 1249, 1213, 1184. 1H NMR (DMSO-d6):
d
2.29 (s, 3H), 2.30 (s,
3H), 3.63 (s, 3H), 6.62 (d, J¼15.9 Hz, 1H), 7.34 (m, 1H), 7.55 (m, 3H),
9.21 (br s, 1H), 9.95 (br s, 1H). 13C NMR (DMSO-d6):
20.3, 52.0,
134.7, 135.3, 135.6, 156.8, 168.0. MS (ESþ) m/z (%) 297.1 (MHþ). Anal.
Calcd for C17H16N2O3 (296.32): C, 68.91; H, 5.44; N, 9.45. Found: C,
69.14; H, 5.53; N, 9.52.
d
120.4, 122.6, 124.2, 126.1, 133.4, 138.8, 142.4, 143.0, 156.7, 164.6,
168.1, 168.2. MS (EI) m/z (%) 336 (Mþ, 3), 247 (33), 205 (60), 163
(100). Anal. Calcd for C15H16N2O7 (336.30): C, 53.57; H, 4.80; N,
8.33. Found: C, 53.61; H, 4.83; N, 8.24.
The hydrazides 1a, 1b were prepared from the acids 6j, 6k fol-
lowing the above general procedure:
4.2.12. Methyl 2-[(2E)-3-(4-fluorophenyl)prop-2-enoyl]hydrazinecar-
boxylate (1a). Reaction time: 1 h 30 min (for 7j) and 17 h. White
platelets; mp 178.5–180.1 ꢀC (EtOAc). Lit. mp 180–183 ꢀC.11 IR (KBr):
3257, 1719, 1663, 1628, 1603, 1524, 1509, 1226. 1H NMR (DMSO-d6):
4.2.6. Methyl 2-[(2E)-3-(2-thienyl)prop-2-enoyl]hydrazinecarboxylate
(8f). Reaction time: 4 h 30 min (for 7f) and 20 h. Off-white needles;
mp 136.1–137.7 ꢀC (EtOAc). IR (KBr): 3346, 3190, 1734, 1719, 1661,
d
3.64 (s, 3H), 6.59 (d, J¼15.9 Hz, 1H), 7.27 (m, 2H), 7.57 (d,
1651, 1616, 1231. 1H NMR (DMSO-d6):
d
3.63 (s, 3H), 6.40 (d,
J¼15.9 Hz, 1H), 7.69 (m, 2H), 9.22 (br s, 1H), 9.93 (br s, 1H). 13C NMR
J¼15.6 Hz, 1H), 7.13 (dd, J1¼5.1 Hz, J2¼3.5 Hz, 1H), 7.44 (d, J¼3.5 Hz,
(DMSO-d6):
d
52.0, 115.9 (d, J¼21.7 Hz), 119.2, 129.9 (d, J¼8.5 Hz),
1H), 7.64 (d, J¼5.1 Hz, 1H), 7.73 (d, J¼15.6 Hz, 1H), 9.21 (br s, 1H),
131.1 (d, J¼3.0 Hz), 139.2, 156.7, 162.9 (d, J¼246.2 Hz), 164.7.
9.88 (br s, 1H). 13C NMR (DMSO-d6):
d 52.0, 117.8, 128.4, 128.5, 131.3,
133.4, 139.5, 156.7, 164.7. MS (EI) m/z (%) 226 (Mþ, 8), 137 (100), 109
(41), 65 (20). Anal. Calcd for C9H10N2O3S (226.25): C, 47.78; H, 4.45;
N, 12.38. Found: C, 47.84; H, 4.52; N, 12.45.
4.2.13. Methyl 2-[(2E)-3-phenylprop-2-enoyl]hydrazinecarboxylate
(1b). Reaction time: 2 h (for 7k) and 19 h. White needles; mp
161.0–162.6 ꢀC (EtOAc). Lit. mp 164–166 ꢀC.11 IR (KBr): 3328, 3193,
1729, 1716, 1672, 1633, 1557, 1232. 1H NMR (DMSO-d6):
d 3.62 (s,
4.2.7. Methyl 2-[(2E)-3-(3-thienyl)prop-2-enoyl]hydrazinecarboxylate
(8g). Reaction time: 4 h 30 min (for 7g) and 19 h 30 min. White
needles; mp 147.8–149.5 ꢀC (EtOAc). IR (KBr): 3343, 3194, 1733,
3H), 6.62 (d, J¼15.9 Hz, 1H), 7.42 (m, 3H), 7.54 (d, J¼15.9 Hz, 1H),
7.61 (m, 2H), 9.18 (br s, 1H), 9.90 (br s, 1H).
1717, 1657, 1621, 1272, 1228. 1H NMR (DMSO-d6):
d
3.63 (s, 3H), 6.46
4.3. General procedure for the transformations of 8 into 9
(d, J¼15.6 Hz, 1H), 7.39 (d, J¼5.1 Hz, 1H), 7.57 (d, J¼15.6 Hz, 1H), 7.62
(dd, J1¼5.1 Hz, J2¼3.0 Hz, 1H), 7.87 (d, J¼3.0 Hz, 1H), 9.18 (br s, 1H),
NBS (1.978 g, 11 mmol) was slowly added to a stirred solution of
the hydrazide 12 (2.343 g, 10 mmol) and pyridine (1.598 g,
20 mmol) in CH2Cl2 (130 mL) at room temperature. The reaction
mixture was then stirred at the same temperature for 10–35 min
(TLC evidence), treated successively with a 12% aqueous solution of
HCl (33 mL), a 5% aqueous solution of Na2S2O3$5H2O (33 mL), sat-
urated aqueous NaHCO3 (33 mL), and H2O (33 mL), and dried over
anhydrous Na2SO4 (for the characterization of the diazene 4d, see
Section 4.3.14). An organic phase containing the diazene 4 was
added dropwise to a stirred suspension of ZrCl4 (3.56 g,15 mmol) in
dry CH2Cl2 (10 mL) at room temperature. After stirring at room
temperature for an additional 1–4.5 h (TLC evidence) the reaction
mixture was quenched with H2O (150 mL) and neutralized with
saturated aqueous NaHCO3. The two phases were separated, and
the aqueous solution was extracted with CH2Cl2 (3ꢁ100 mL). The
organic phase was dried over anhydrous Na2SO4 and evaporated to
dryness to give the pyrazol-3-one 9 in a good-to-excellent yield.
9.86 (br s, 1H). 13C NMR (DMSO-d6):
d 52.0, 118.7, 125.2, 127.8, 128.2,
134.4, 137.6, 156.7, 165.2. MS (EI) m/z (%) 226 (Mþ, 4), 137 (100), 109
(44), 65 (20). Anal. Calcd for C9H10N2O3S (226.25): C, 47.78; H, 4.45;
N, 12.38. Found: C, 47.91; H, 4.52; N, 12.36.
4.2.8. Methyl 2-[(2E)-3-(4-nitrophenyl)prop-2-enoyl]hydrazinecarboxy-
late (8h). Reaction time: 4 h (for 7h) and 17 h. Off-white needles;
mp 238–241 ꢀC (EtOAc/MeOH). IR (KBr): 3287, 1744, 1721, 1662,
1623, 1511, 1350, 1252. 1H NMR (DMSO-d6):
d 3.67 (s, 3H), 6.84 (d,
J¼15.9 Hz, 1H), 7.69 (d, J¼15.9 Hz, 1H), 7.90 and 8.28 (AA0XX0,
J¼8.9 Hz, 4H), 9.31 (br s, 1H), 10.11 (br s, 1H). 13C NMR (DMSO-d6):
d
52.0, 123.6, 124.1, 128.8, 138.1, 141.0, 147.7, 156.6, 164.2. MS (ESþ)
m/z (%) 266.1 (MHþ). Anal. Calcd for C11H11N3O5 (265.23): C, 49.81;
H, 4.18; N, 15.84. Found: C, 49.94; H, 3.98; N, 15.86.
4.2.9. Methyl 2-[(2E)-3-(4-chlorophenyl)prop-2-enoyl]hydrazinecarboxy-
late (8i). Reaction time: 4 h (for 7i) and 16 h. White platelets; mp
192.0–193.2 ꢀC (EtOAc). IR (KBr): 3258, 3028, 1716, 1665, 1634,
4.3.1. Methyl 3-oxo-5-(3,4,5-trimethoxyphenyl)-2,3-dihydro-1H-pyr-
azole-1-carboxylate (9a). Reaction time: (oxidation) 10 min, (cycli-
zation) 2 h. Off-white amorphous powder; mp 188.7–191.0 ꢀC
(EtOAc). IR (KBr): 1757, 1585, 1533, 1447, 1362, 1346, 1267, 1132. 1H
1523, 1492, 1245. 1H NMR (DMSO-d6):
d 3.65 (s, 3H), 6.66 (d,
J¼15.9 Hz, 1H), 7.49 and 7.65 (AA0XX0, J¼8.6 Hz, 4H), 7.57 (d,
J¼15.9 Hz, 1H), 9.25 (br s, 1H), 9.97 (br s, 1H). 13C NMR (DMSO-d6):
d
52.0, 120.1, 129.0, 129.4, 133.5, 134.3, 139.1, 156.7, 164.6. MS (ESþ)
NMR (DMSO-d6): d 3.72 (s, 3H), 3.80 (s, 9H), 6.04 (s,1H), 6.79 (s, 2H),

8694
B. Burja et al. / Tetrahedron 65 (2009) 8690–8696
10.97 (br s, 1H). 13C NMR (DMSO-d6):
d
53.8, 56.1, 60.1, 100.8, 106.9,
11.01 (br s, 1H). 13C NMR (DMSO-d6):
d 53.9, 100.6, 125.2, 125.9,
126.2, 138.0, 147.7, 149.9, 152.3, 162.4. MS (EI) m/z (%) 308 (Mþ, 100),
293 (48), 265 (13), 177 (10). Anal. Calcd for C14H16N2O6 (308.29): C,
54.54; H, 5.23; N, 9.09. Found: C, 54.69; H, 5.44; N, 8.84.
128.9, 130.4, 142.8, 150.0, 162.5. MS (EI) m/z (%) 224 (Mþ, 100), 179
(37), 151 (17), 109 (53). Anal. Calcd for C9H8N2O3S (224.24): C,
48.21; H, 3.60; N, 12.49. Found: C, 47.92; H, 3.61; N, 12.20.
4.3.2. Methyl 5-(2,3-dimethoxyphenyl)-3-oxo-2,3-dihydro-1H-pyr-
azole-1-carboxylate (9b). Reaction time: (oxidation) 10 min, (cy-
clization) 4 h 30 min. White platelets; mp 218–220 ꢀC (MeOH). IR
(KBr): 1754, 1589, 1532, 1434, 1341, 1269, 1000, 790. 1H NMR
4.3.8. Methyl 5-(4-nitrophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-
carboxylate (9h). Reaction time: (oxidation) 5 min, (cyclization)
1 h. White amorphous powder; mp 202–204 ꢀC (EtOAc/MeOH). IR
(KBr): 3030, 1750, 1586, 1518, 1442, 1337, 1283, 1138. 1H NMR
(DMSO-d6):
d
3.56 (s, 3H), 3.70 (s, 3H), 3.83 (s, 3H), 5.93 (s, 1H), 6.84
(DMSO-d6): d
3.77 (s, 3H), 6.19 (s, 1H), 7.77 and 8.24 (AA0XX0,
(dd, J1¼7.2 Hz, J2¼1.8 Hz, 1H), 7.10 (m, 2H), 10.91 (br s, 1H). 13C NMR
J¼8.7 Hz, 4H), 11.13 (br s, 1H). 13C NMR (DMSO-d6):
d 54.1, 102.0,
(DMSO-d6):
d
53.8, 55.8, 60.1, 100.5, 113.9, 121.6, 123.5, 125.5, 143.4,
122.8, 130.4, 137.2, 145.4, 147.4, 149.9, 162.6. MS (ESþ) m/z (%) 264.1
(MHþ). Anal. Calcd for C11H9N3O5 (263.21)$1/5H2O: C, 49.52; H,
3.55; N, 15.75. Found: C, 49.40; H, 3.25; N, 15.54.
146.2, 149.7, 152.0, 162.4. MS (EI) m/z (%) 278 (Mþ, 100), 247 (16),
188 (33), 161 (47). Anal. Calcd for C13H14N2O5 (287.26): C, 56.11; H,
5.07; N, 10.07. Found: C, 55.96; H, 4.94; N, 9.95.
4.3.9. Methyl 5-(4-chlorophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-
carboxylate (9i). Reaction time: (oxidation) 5 min, (cyclization) 1 h.
White needles; mp 196.8–199.0 ꢀC (EtOAc). IR (KBr): 1753, 1609,
4.3.3. Methyl 5-(4-acetoxyphenyl)-3-oxo-2,3-dihydro-1H-pyrazole-
1-carboxylate (9c). Reaction time: (oxidation) 10 min, (cyclization)
4 h. White needles; mp 192.8–194.8 ꢀC (EtOAc). IR (KBr): 1750,
1590, 1524, 1439, 1368, 1336, 1284. 1H NMR (DMSO-d6):
d
3.78 (s,
1536, 1440, 1375, 1344, 1238, 1218, 1204. 1H NMR (DMSO-d6):
d 2.29
3H), 6.06 (s, 1H), 7.48 (m, 4H), 11.07 (br s, 1H). 13C NMR (DMSO-d6):
(s, 3H), 3.77 (s, 3H), 6.05 (s,1H), 7.17 and 7.50 (AA0XX0, J¼8.4 Hz, 4H),
d
53.9, 101.1, 127.7, 129.6, 130.8, 133.6, 146.4, 149.9, 162.5. MS (ESþ)
11.06 (br s, 1H). 13C NMR (DMSO-d6):
d
20.8, 53.9, 101.0, 121.2, 128.2,
m/z (%) 253.0 (MHþ). Anal. Calcd for C11H9ClN2O3 (252.66): C,
130.2, 147.0, 150.0, 150.8, 162.5, 169.1. MS (EI) m/z (%) 276 (Mþ, 12),
234 (100), 189 (35), 118 (38). Anal. Calcd for C13H12N2O5 (276.24): C,
56.52; H, 4.38; N, 10.14. Found: C, 56.48; H, 4.47; N, 9.87.
52.29; H, 3.59; N, 11.09. Found: C, 52.14; H, 3.37; N, 11.01.
4.3.10. Methyl 4-methyl-3-oxo-5-phenyl-2,3-dihydro-1H-pyrazole-
1-carboxylate (9l). Reaction time: (oxidation) 20 min, (cyclization)
1 h 15 min. White cubes; mp 156.1–157.2 ꢀC (EtOAc). IR (KBr): 2966,
4.3.4. Methyl 5-(4-acetoxy-3-methoxyphenyl)-3-oxo-2,3-dihydro-1H-
pyrazole-1-carboxylate (9d). Reaction time: (oxidation) 35 min,
(cyclization) 1 h 5 min. White platelets; mp 192.2–194.1 ꢀC (EtOAc).
IR (KBr): 1766, 1595, 1587, 1326, 1224, 1210, 1139, 1118. 1H NMR
1755, 1540, 1445, 1336, 1280, 1213, 1177. 1H NMR (DMSO-d6):
d
1.74
(s, 3H), 3.71 (s, 3H), 7.38 (m, 5H), 11.12 (br s, 1H). 13C NMR (DMSO-
d6):
d 6.8, 53.5, 107.9, 127.8, 128.3, 129.4, 130.8, 143.2, 149.9, 162.3.
(DMSO-d6):
d
2.28 (s, 3H), 3.77 (s, 3H), 3.79 (s, 3H), 6.07 (s, 1H), 7.03
MS (EI) m/z (%) 232 (Mþ, 100), 187 (62), 115 (52), 77 (22). Anal. Calcd
for C12H12N2O3 (232.24): C, 62.06; H, 5.21; N, 12.06. Found: C,
62.29; H, 5.20; N, 12.19.
(dd, J1¼8.1 Hz, J2¼1.8 Hz, 1H), 7.10 (d, J¼8.1 Hz, 1H), 7.26 (d,
J¼1.8 Hz, 1H), 11.00 (br s, 1H). 13C NMR (DMSO-d6):
d 20.4, 53.9,
56.0, 101.1, 113.9, 121.4, 122.1, 129.4, 139.7, 147.1, 149.9, 150.1, 162.5,
168.5. MS (EI) m/z (%) 306 (Mþ, 4), 264 (100), 205 (12), 148 (16).
Anal. Calcd for C14H14N2O6 (306.27): C, 54.90; H, 4.61; N, 9.15.
Found: C, 54.92; H, 4.66; N, 8.93.
4.3.11. Methyl 4,5-diphenyl-3-oxo-2,3-dihydro-1H-pyrazole-1-car-
boxylate (9m). Reaction time: (oxidation) 5 min, (cyclization) 1 h.
White needles; mp 213–216 ꢀC (MeOH). IR (KBr): 1762, 1754, 1543,
1440, 1347, 1262, 1160, 703. 1H NMR (DMSO-d6):
d
3.72 (s, 3H), 7.17
4.3.5. Methyl 5-(3,4-diacetoxyphenyl)-3-oxo-2,3-dihydro-1H-pyrazole-
1-carboxylate (9e). Reaction time: (oxidation) 25 min, (cyclization)
1 h 45 min. White needles; mp 186.5–187.8 ꢀC (EtOAc). IR (KBr):
1770, 1754, 1373, 1359, 1331, 1245, 1214, 1185. 1H NMR (DMSO-d6):
(m, 5H), 7.34 (m, 5H), 11.50 (br s, 1H). 13C NMR (DMSO-d6):
d
53.8,
112.5, 126.7, 127.88, 127.92, 128.5, 128.7, 129.8, 130.0, 130.8, 142.8,
149.7, 160.7. MS (ESþ) m/z (%) 295.1 (MHþ). Anal. Calcd for
C17H14N2O3 (294.30): C, 69.38; H, 4.79; N, 9.52. Found: C, 69.64; H,
4.65; N, 9.55.
The pyrazole-3-ones 2a, 2b were prepared from the hydrazides
1a, 1b following the above general procedure:
d
2.28 (s, 3H), 2.30 (s, 3H), 3.76 (s, 3H), 6.07 (s, 1H), 7.29 (dd,
J1¼7.8 Hz, J2¼0.9 Hz, 1H), 7.39 (m, 2H), 11.01 (br s, 1H). 13C NMR
(DMSO-d6):
d 20.29, 20.35, 54.0, 101.3, 123.0, 124.4, 127.3, 129.1,
141.3, 142.4, 146.0, 149.9, 162.5, 168.15, 168.16. MS (EI) m/z (%) 334
(Mþ, 4), 292 (30), 250 (100), 205 (19). Anal. Calcd for C15H14N2O7
(334.28): C, 53.89; H, 4.22; N, 8.38. Found: C, 53.63; H, 4.03; N, 8.12.
4.3.12. Methyl 5-(4-fluorophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-
1-carboxylate (2a). Reaction time: (oxidation) 5 min, (cyclization)
1 h 15 min. White needles; mp 191.7–193.8 ꢀC (EtOAc). Lit. mp 175–
177 ꢀC.11 IR (KBr): 1749, 1613, 1535, 1440, 1374, 1346, 1223, 783. 1H
4.3.6. Methyl 3-oxo-5-(2-thienyl)-2,3-dihydro-1H-pyrazole-1-car-
boxylate (9f). Reaction time: (oxidation) 10 min, (cyclization) 3 h
30 min. Light-brown plates; mp 176.3–177.9 ꢀC (EtOAc). IR (KBr):
1747, 1603, 1443, 1374, 1352, 1322, 1211, 704. 1H NMR (DMSO-d6):
NMR (DMSO-d6):
d
3.77 (s, 3H), 6.03 (s, 1H), 7.23 (m, 2H), 7.51 (m,
53.9, 101.0, 114.6 (d,
2H), 11.05 (br s, 1H). 13C NMR (DMSO-d6):
d
J¼21.7 Hz),127.2 (d, J¼3.2 Hz),131.2 (d, J¼8.4 Hz), 146.7, 149.9,162.3
d
3.85 (s, 3H), 6.16 (s, 1H), 7.12 (dd, J1¼5.1 Hz, J2¼3.8 Hz, 1H), 7.43
(d, J¼244.4 Hz), 162.5.
(dd, J1¼3.8 Hz, J2¼0.9 Hz, 1H), 7.68 (dd, J1¼5.1 Hz, J2¼0.9 Hz, 1H),
11.09 (br s,1H). 13C NMR (DMSO-d6):
d
54.1,101.4,127.0,128.2,129.8,
4.3.13. Methyl 3-oxo-5-phenyl-2,3-dihydro-1H-pyrazole-1-carboxyl-
ate (2b). Reaction time: (oxidation) 5 min, (cyclization) 1 h. White
cubes; mp 182.6–184.9 ꢀC (EtOAc). Lit. mp 155–159 ꢀC.11 IR (KBr):
1748, 1596, 1530, 1442, 1367, 1334, 1134, 766. 1H NMR (DMSO-d6):
130.0, 140.6, 150.0, 162.4. MS (EI) m/z (%) 224 (Mþ, 100), 179 (33),
109 (62), 65 (44). Anal. Calcd for C9H8N2O3S (224.24): C, 48.21; H,
3.60; N, 12.49. Found: C, 48.18; H, 3.58; N, 12.45.
d
3.76 (s, 3H), 6.02 (s, 1H), 7.42 (m, 5H), 11.03 (br s, 1H). 13C NMR
4.3.7. Methyl 3-oxo-5-(3-thienyl)-2,3-dihydro-1H-pyrazole-1-car-
boxylate (9g). Reaction time: (oxidation) 10 min, (cyclization) 1 h
10 min. Off-white needles; mp 184.0–186.2 ꢀC (EtOAc). IR (KBr):
1749, 1605, 1557, 1438, 1378, 1355, 1334, 777. 1H NMR (DMSO-d6):
(DMSO-d6): d 53.8,100.8,127.7,128.7,128.9,130.8,147.8,150.0,162.5.
The diazene 4d was obtained by the oxidation of the hydrazide
8d in 99% yield:
d
3.81 (s, 3H), 6.07 (s, 1H), 7.29 (dd, J1¼5.1 Hz, J2¼1.2 Hz, 1H), 7.54
4.3.14. Methyl 2-[(2E)-3-(4-acetoxy-3-methoxyphenyl)prop-2-enoyl]-
diazenecarboxylate (4d). Reaction time: 5 min. Orange amorphous
(dd, J1¼3.0 Hz, J2¼5.1 Hz, 1H), 7.75 (dd, J1¼3.0 Hz, J2¼1.2 Hz, 1H),

B. Burja et al. / Tetrahedron 65 (2009) 8690–8696
8695
powder; mp 76.8–84.4 ꢀC (CH2Cl2/i-Pr2O). IR (KBr): 1763, 1692,
1509, 1261, 1217, 1199, 1156, 1121. 1H NMR (DMSO-d6):
2.29 (s, 3H),
1473, 1384, 1293, 1242. 1H NMR (DMSO-d6):
d
5.83 (s, 1H), 6.80 (d,
d
J¼8.1 Hz,1H), 7.03 (dd, J1¼8.1 Hz, J2¼2.1 Hz,1H), 7.10 (d, J¼2.1 Hz,1H),
3.86 (s, 3H), 4.10 (s, 3H), 7.18 (d, J¼16.2 Hz, 1H), 7.21 (d, J¼8.1 Hz,
9.23 (br s, 4H). 13C NMR (DMSO-d6):
d 86.6, 113.5, 116.2, 117.6, 120.1,
1H), 7.44 (dd, J1¼8.1 Hz, J2¼1.8 Hz, 1H), 7.66 (d, J¼1.8 Hz, 1H), 7.86
145.7, 146.0, 146.9, 159.9. MS (EI) m/z (%) 192 (Mþ, 100), 163 (8), 135
(41), 89 (10). HRMS calcd for C9H8N2O3 (Mþ): 192.0535. Found:
192.0537.
(d, J¼16.2 Hz, 1H). 13C NMR (DMSO-d6):
d 20.3, 55.7, 56.1, 112.7,
116.3, 123.2, 123.4, 132.4, 142.4, 150.4, 151.3, 160.6, 168.2, 180.1. MS
(EI) m/z (%) 308 ((Mþ2H)þ, 0.3), 219 (38), 177 (100), 145 (27). Anal.
Calcd for C14H14N2O6 (306.27): C, 54.90; H, 4.61; N, 9.15. Found: C,
54.79; H, 4.54; N, 8.72. HRMS calcd for C14H15N2O6 (MHþ):
307.0930. Found: 307.0922.
4.4.6. 5-(2-Thienyl)-1,2-dihydro-3H-pyrazol-3-one (11f). Reaction
time: 3 h 10 min. Gray amorphous powder; mp 200–201 ꢀC
(EtOAc). Lit. mp 203–204 ꢀC.5b IR (KBr): 2590, 1615, 1571, 1524,
1440, 770, 743, 712. 1H NMR (DMSO-d6):
d 5.69 (s, 1H), 7.07 (dd,
4.4. Hydrolysis of 1-methoxycarbonylpyrazol-3-ones into 11
J1¼5.1 Hz, J2¼3.6 Hz, 1H), 7.33 (dd, J1¼3.6 Hz, J2¼1.1 Hz, 1H), 7.46
(dd, J1¼5.1 Hz, J2¼1.1 Hz, 1H), 10.23 (br s, 2H). Anal. Calcd for
C7H6N2OS (166.20): C, 50.59; H, 3.64; N, 16.86. Found: C, 50.38; H,
3.64; N, 16.56.
A methanolic solution of NaOH (2 M, 6 mL; 12 mL in the case of
9e) was added to a stirred mixture of 1-methoxycarbonylpyrazol-3-
one (5 mmol) in CH2Cl2/MeOH (9:1; 20 mL) at room temperature.
Stirring was continued at the same temperature for an additional
1–4.5 h and the reaction mixture was evaporated to dryness. The
residue was treated with water (50 mL), acidified with aqueous HCl
(1:2, v/v), and extracted with EtOAc (4ꢁ100 mL). The combined
EtOAc extracts were dried over anhydrous sodium sulfate and
evaporated to dryness to give unprotected pyrazol-3-ones 11. A
modified procedure (applied for the isolation of 11c–11e): the re-
action mixture after the addition of aqueous HCl was evaporated to
dryness, treated with isopropanol (75 mL), filtered through a short
column of silica gel, and evaporated to dryness.
4.4.7. 5-(3-Thienyl)-1,2-dihydro-3H-pyrazol-3-one (11g). Reaction
time: 4 h 30 min. Light-pink small needles; mp 215–217 ꢀC (EtOAc).
IR (KBr): 2722, 1616, 1589, 1526, 1491, 777, 717, 702. 1H NMR
(DMSO-d6):
d
5.82 (s, 1H), 7.44 (dd, J1¼5.0 Hz, J2¼0.9 Hz, 1H), 7.59
(dd, J1¼5.0 Hz, J2¼2.9 Hz, 1H), 7.74 (dd, J1¼2.9 Hz, J2¼0.9 Hz, 1H),
10.87 (m, 2H). 13C NMR (DMSO-d6):
d 87.1, 120.5, 125.5, 126.9, 132.0,
139.5, 160.9. MS (EI) m/z (%) 166 (Mþ, 100), 137 (5), 109 (48), 65 (11).
Anal. Calcd for C7H6N2OS (166.20): C, 50.59; H, 3.64; N, 16.86.
Found: C, 50.34; H, 3.67; N, 16.58.
4.4.8. 5-(4-Nitrophenyl)-1,2-dihydro-3H-pyrazol-3-one (11h). Re-
action time: 2 h 30 min. Yellow amorphous powder; mp 240–
243 ꢀC (EtOAc). Lit. mp 248–249 ꢀC.17 IR (KBr): 3369, 1604,
4.4.1. 5-(3,4,5-Trimethoxyphenyl)-1,2-dihydro-3H-pyrazol-3-one
(11a). Reaction time: 4 h. Pale yellow amorphous powder; mp
233–235 ꢀC (EtOAc). Lit. mp 230–232 ꢀC.16 IR (KBr): 3327, 1595,
1575, 1541, 1511, 1349, 1331, 855. 1H NMR (DMSO-d6):
d 6.07 (s,
1572, 1527, 1501, 1260, 1247, 1136. 1H NMR (DMSO-d6):
d
3.67 (s,
1H), 7.95 and 8.25 (AA0XX0, J¼8.7 Hz, 4H), 10.30 (br s, 1H), 12.47
3H), 3.82 (s, 6H), 5.91 (s, 1H), 6.97 (s, 2H), 9.81 (br s, 1H), 11.89 (br s,
1H). Anal. Calcd for C12H14N2O4 (250.25): C, 57.59; H, 5.64; N, 11.19.
Found: C, 57.30; H, 5.54; N, 10.80.
(br s, 1H).
4.4.9. 5-(4-Chlorophenyl)-1,2-dihydro-3H-pyrazol-3-one (11i). Re-
action time: 2 h. White needles; mp 243–245 ꢀC (EtOAc/MeOH). Lit.
mp 242 ꢀC.18 IR (KBr): 2810, 1626, 1555, 1519, 1493, 1467, 1092, 797. 1H
4.4.2. 5-(2,3-Dimethoxyphenyl)-1,2-dihydro-3H-pyrazol-3-one
(11b). Reaction time: 4 h. Pale yellow small cubes; mp 176.5–
177.9 ꢀC (EtOAc). IR (KBr): 3352, 1568, 1536, 1506, 1482, 1266, 1055,
NMR (DMSO-d6):
d
6.40 (s, 1H), 7.60 and 8.00 (AA0XX0, J¼8.6 Hz, 4H),
13.76 (br s, 2H).13C NMR (DMSO-d6):
d 88.2,126.2,128.3,129.2,135.0,
771. 1H NMR (DMSO-d6):
d
3.71 (s, 3H), 3.83 (s, 3H), 5.95 (s, 1H), 7.01
145.4, 158.1.
(dd, J1¼8.1 Hz, J2¼1.5 Hz, 1H), 7.10 (dd, J1¼8.1 Hz, J2¼7.8 Hz, 1H),
7.24 (dd, J¼7.8, 1.5 Hz, 1H), 10.73 (br s, 2H). 13C NMR (DMSO-d6):
4.4.10. 5-(4-Fluorophenyl)-1,2-dihydro-3H-pyrazol-3-one (11j). Re-
action time: 2 h 30 min. White amorphous powder; mp 230–
235 ꢀC. Lit. mp 168–170 ꢀC.19 IR (KBr): 1621, 1601, 1553, 1514, 1493,
d
55.8, 59.7, 89.8, 112.3, 118.7, 123.9, 124.2, 139.2, 145.5, 153.1, 161.0.
MS (EI) m/z (%) 220 (Mþ, 100), 189 (21), 175 (19), 134 (20). HRMS
calcd for C11H12N2O3 (Mþ): 220.0848. Found: 220.0850.
1451, 1224, 844. 1H NMR (DMSO-d6):
d
5.93 (s, 1H), 7.26 (m, 2H),
7.75 (m, 2H), 10.18 (br s, 2H). 13C NMR (DMSO-d6):
d
86.8, 115.7 (d,
4.4.3. 5-(4-Hydroxyphenyl)-1,2-dihydro-3H-pyrazol-3-one (11c). Re-
action time: 4 h. Large off-white plates; mp 273–277 ꢀC (EtOAc/
MeOH). IR (KBr): 2957, 1626, 1601, 1567, 1536, 1507, 1470, 1265. 1H
J¼21.6 Hz), 126.9 (d, J¼8.2 Hz), 127.3 (d, J¼2.7 Hz), 143.1, 160.6, 161.7
(d, J¼244.8 Hz). MS (ESþ) m/z (%) 179 (MHþ). HRMS calcd for
C9H8FN2O (MHþ): 179.0621. Found: 179.0626.
NMR (DMSO-d6):
d
6.12 (s,1H), 6.89 and 7.70 (AA0XX0, J¼8.7 Hz, 4H),
10.06 (br s, 3H). 13C NMR (DMSO-d6):
d
86.7, 116.0, 117.6, 128.3,
4.4.11. 5-Phenyl-1,2-dihydro-3H-pyrazol-3-one (11k). Reaction time:
2 h 30 min. White amorphous powder; mp 237–240 ꢀC (EtOAc). Lit.
mp 236–238 ꢀC.20 IR (KBr): 3061, 1624, 1600, 1541, 1510, 1490, 1465,
147.4, 158.0, 159.8. MS (EI) m/z (%) 178 ((MH2)þ, 75), 147 (100), 119
(34), 91 (25). HRMS calcd for C9H9N2O2 (MHþ): 177.0664. Found:
177.0670.
758. 1H NMR (DMSO-d6):
d 5.80 (br s, 2H), 6.02 (s, 1H), 7.43 (m, 3H),
7.73 (m, 2H).
4.4.4. 5-(4-Hydroxy-3-methoxyphenyl)-1,2-dihydro-3H-pyrazol-3-
one (11d). Reaction time: 2 h 25 min. Light-brown oil. IR (KBr):
3169, 1633, 1623, 1608, 1514, 1479, 1289, 1266. 1H NMR (DMSO-d6):
4.4.12. 4-Methyl-5-phenyl-1,2-dihydro-3H-pyrazol-3-one (11l). Re-
action time: 1 h 20 min. White cubes; mp 206–212 ꢀC (EtOAc). Lit.
mp 201–205 ꢀC.21 IR (KBr): 3272, 1619, 1599, 1535, 1509, 1478, 767,
d
3.91 (s, 3H), 6.31 (s, 1H), 6.99 (d, J¼8.3 Hz, 1H), 7.40 (dd,
J1¼8.3 Hz, J2¼1.5 Hz, 1H), 7.62 (d, J¼1.5 Hz, 1H), 13.16 (br s, 3H). 13
C
694. 1H NMR (DMSO-d6):
d 1.99 (s, 3H), 7.43 (m, 5H), 9.52 (br s, 1H),
NMR (DMSO-d6):
d
56.1, 86.9, 110.6, 116.0, 117.9, 120.3, 147.6,
11.67 (br s, 1H). Anal. Calcd for C10H10N2O (174.20): C, 68.95; H,
5.79; N, 16.08. Found: C, 68.96; H, 5.91; N, 16.18.
148.1, 149.2, 157.9. MS (EI) m/z (%) 206 (Mþ, 100), 191 (16), 163 (15),
149 (46). HRMS calcd for C10H10N2O3 (Mþ): 206.0691. Found:
206.0686.
4.4.13. 4,5-Diphenyl-1,2-dihydro-3H-pyrazol-3-one (11m). Reaction
time: 3 h. White platelets; mp 235–236 ꢀC (EtOAc/heptane). Lit. mp
236–238 ꢀC.22 IR (KBr): 3470, 3406, 3314, 3250,1616,1513, 758, 695.
4.4.5. 5-(3,4-Dihydroxyphenyl)-1,2-dihydro-3H-pyrazol-3-one
(11e). Reaction time: 4 h. Brown oil. IR (KBr): 3151, 1626, 1531, 1514,
1H NMR (DMSO-d6): 7.25 (m, 10H), 11.08 (br s, 2H). 13C NMR
d

8696
B. Burja et al. / Tetrahedron 65 (2009) 8690–8696
7. Patel, M. V.; Bell, R.; Majest, S.; Henry, R.; Kolasa, T. J. Org. Chem. 2004, 69, 7058–
d 102.8, 125.6, 127.5, 128.1, 128.6, 128.9, 130.7, 132.8,
(DMSO-d6):
139.8, 159.1.
7065.
8. Bran˜a, M. F.; Gradillas, A.; Ovalles, A. G.; Lo´ pez, B.; Acero, N.; Llinares, F.;
Mingarro, D. M. Bioorg. Med. Chem. 2006, 14, 9–16.
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Aschenbrenner, A. Bioorg. Med. Chem. Lett. 2008, 18, 4022–4026.
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Acknowledgements
The Ministry of Higher Education, Science and Technology of
Slovenia and the Slovenian Research Agency are gratefully ac-
knowledged for their financial support (P1-0230-103). We would
11. Prata, J. V.; Clemente, D.-T. S.; Prabhakar, S.; Lobo, A. M.; Mourato, I.; Branco, P. S.
J. Chem. Soc., Perkin Trans. 1 2002, 513–528.
ˇ
ˇ
like to thank Dr. Bogdan Kralj and Dr. Dusan Zigon (Mass Spec-
ˇ
ˇ
12. (a) Kosmrlj, J.; Kocevar, M.; Polanc, S. Synlett 1996, 652–654; (b) Pieters, L.;
ˇ ˇ
ꢀ
trometry Center, Jozef Stefan Institute, Ljubljana, Slovenia) for re-
ˇ
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Kosmrlj, J.; Lenarsic, R.; Kocevar, M.; Polanc, S. Arkivoc 2001, V, 42–50; (c) Po-
ˇ
ˇ ˇ
lanc, S. J. Heterocycl. Chem. 2005, 42, 401–412; (d) Kovac, A.; Majce, V.; Lenarsic,
R.; Bombek, S.; Bostock, J.; Chopra, I.; Polanc, S.; Gobec, S. Bioorg. Med. Chem.
cording the mass spectra.
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Lett. 2007, 17, 2047–2054; (e) Stropnik, T.; Bombek, S.; Kocevar, M.; Polanc, S.
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