Eclectic 1-Aryl-1,2-diazabuta-1,3-dienes: Valuable tools for the preparation of pyrrol-2-ones, 1-arylpyrazoles, 2-(3-oxopyrazol-4-yl)malonates and 4-(2-oxopyrrol-3-yl)pyrazol-3-ones

Article abstract of DOI:10.1055/s-2002-33334

1-Aryl-1,2-diazabuta-1,3-dienes react with dimethyl malonate to give hydrazonic intermediates that in turn are converted into pyrrol-2-ones, 1-arylpyrazoles and 2-(3-oxopyrazol-4-yl)malonates. The latter compounds represent an useful entry to 4-(2-oxopyrrol-3-yl)pyrazol-3-ones, by means of the addition of another molecule of 1,2-diazabuta-1,3-diene and subsequent cyclization of the adducts.

Full text of DOI:10.1055/s-2002-33334

1546
PAPER
Eclectic 1-Aryl-1,2-diazabuta-1,3-dienes: Valuable Tools for the Preparation
of Pyrrol-2-ones, 1-Arylpyrazoles, 2-(3-Oxopyrazol-4-yl)malonates and
4-(2-Oxopyrrol-3-yl)pyrazol-3-ones
1
-Aryl-1,2-diazabu
r
ta-1,3-
d
a
ienes zio A. Attanasi, Lucia De Crescentini, Gianfranco Favi, Paolino Filippone,* Fabio Mantellini,
Stefania Santeusanio
Istituto di Chimica Organica, Università di Urbino, Piazza della Repubblica 13, 61029 Urbino, Italy
Fax +39(722)2907; E-mail: attanasi@uniurb.it
Received 22 March 2002; revised 26 April 2002
of sodium methoxide we obtained pyrrol-2-ones,6 using
CuCl2 or Cu(OTf)2 we prepared 1-arylpyrazoles, while in
acidic medium we isolated 2-(3-oxopyrazol-4-yl)mal-
onates.
Abstract: 1-Aryl-1,2-diazabuta-1,3-dienes react with dimethyl ma-
lonate to give hydrazonic intermediates that in turn are converted
into pyrrol-2-ones, 1-arylpyrazoles and 2-(3-oxopyrazol-4-yl)mal-
onates. The latter compounds represent an useful entry to 4-(2-ox-
opyrrol-3-yl)pyrazol-3-ones, by means of the addition of another
molecule of 1,2-diazabuta-1,3-diene and subsequent cyclization of
the adducts.
Furthermore, we have also investigated the subsequent
formation of 4-(2-oxopyrrol-3-yl)pyrazol-3-ones starting
from these latter substrates and a further molecule of 1,2-
diazabuta-1,3-diene.
Key words: 1,2-diazabuta-1,3-dienes, Michael additions, cycliza-
tions, pyrroles, pyrazoles
1-Aryl-1,2-diazabuta-1,3-dienes 1a–c are prepared from
methyl or ethyl 2-chloroacetoacetate with phenyl- or 4-
chlorophenylhydrazine, according to the typical proce-
dures described in literature.7
The azo-ene system of 1,2-diazabuta-1,3-dienes can be in-
fluenced by the presence of electron-rich or electron-poor
groups on terminal carbon and/or nitrogen.1–6 Although
the terminal carbon remains the preferential target of nu-
cleophilic attacks, electron-donating groups reduce the
electrophilic character of this atom, while electron-with-
drawing ones enhance it. The reaction of these substrates
with activated methylene compounds generates a variety
of -substituted hydrazones as a consequence of 1,4-con-
jugated addition (Michael-type). The formation of this
new carbon-carbon single bond is important both in itself
and in view of subsequent five or six-membered cycliza-
tion processes.3,4,6
In the presence of sodium methoxide (0.5 equiv) in tetra-
hydrofuran at room temperature, the reaction be-
tween compounds 1a–c and dimethyl malonate gives
rise to
-substituted hydrazone derivatives 2a–c
(Scheme 1). Yields and reaction times of 2a–c are listed in
Table 1.
Here we report on the reaction of 1-aryl-1,2-diazabuta-
1,3-dienes with dimethyl malonate. The presence of an
aryl substituent instead of amido or ester group on the ter-
minal nitrogen atom of the azo-ene system reduces its
electrophilic character. In fact, we observed that the addi-
tion of dimethyl malonate to 1-aryl-1,2-diazabuta-1,3-
dienes to give hydrazonic intermediates proceeds with
lower yields and longer times with respect to the same re-
actions carried out using 1-aminocarbonyl- or 1-alkoxy-
carbonyl-1,2-diazabuta-1,3-dienes as described by some
of us in a previous work.6
Scheme 1
Table 1 Yields and Reaction Times Required for Hydrazones 2a–c
Starting R1
Material
R2
Product Reaction Yielda
Time (h) (%)
At the same time, the lack of electron-withdrawing groups
on the nitrogen substantially influences the subsequent
cyclization process of hydrazone intermediates. These lat-
ter compounds were demonstrated to be useful as versatile
tools in the synthesis of different classes of heterocycles,
using different reaction conditions. In fact, in the presence
1a
1b
1c
Me
H
2a
2b
2c
50
47
54
59
61
51
Et
H
Me
Cl
a Yield of pure isolated products.
Synthesis 2002, No. 11, Print: 22 08 2002.
Art Id.1437-210X,E;2002,0,11,1546,1552,ftx,en;P01202SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Pyrrol-2-ones, 1-Arylpyrazoles, 2-(3-Oxopyrazol-4-yl)malonates and 4-(2-Oxopyrrol-3-yl)pyrazol-3-ones
1547
The configuration of C=N double bond of these interme-
diates was determined by NOE experiments, carried out
on compound 2c. It shows considerable NOE enhance-
ment of NH by irradiation of CH3, and vice versa. This ev-
idence suggests the proximity of these two groups, in
agreement with E-configuration of the C=N centre.
Table 2 Yields and Reaction Times Required for Pyrrol-2-ones
3a–c
Starting R1
Material
R2
Product Reaction Yielda
Time (h) (%)
2a
2b
2c
Me
H
3a
3b
3c
5.0
4.5
5.5
71
68
75
It is worth underlining that these common and useful in-
termediates like 2a–c can be submitted to interesting
transformations, by only varying the reaction conditions,
due to the lack of a strong electron-withdrawing group on
the nitrogen atom in position 1.
Et
H
Me
Cl
a Yield of pure isolated products based on 2a–c.
As expected, the treatment of compounds 2a–c with sodi-
um methoxide (0.3 equiv) in tetrahydrofuran at room tem-
perature leads to pyrrol-2-ones 3a–c6 by means of an
intramolecular nucleophilic attack of the central hydra-
zone nitrogen atom to the ester group of malonate, with
consequent loss of an alcohol molecule (Scheme 2, path
a). Yields and reaction times of 3a–c are listed in Table 2.
new, mild and simple route to 1-arylpyrazoles which con-
tributes to increase the literature examples reported for
their synthesis.8
We also attempted to submit the hydrazones, previously
prepared from 1-aminocarbonyl- or 1-alkoxycarbonyl-
1,2-diazabuta-1,3-dienes and dimethyl malonate,6 to the
same treatment, but no reaction was detected.
In the presence of CuCl2 or Cu(OTf)2 in tetrahydrofuran
at room temperature, the same hydrazones 2a–c are con-
verted into 1-arylpyrazoles 4a–c (Scheme 2, path b). The
use of CuCl2 rather than of Cu(OTf)2 is more convenient
because of the higher yields and faster reaction times (see
Table 3), as well as lower costs. This method represents a
The same compounds 2a–c, in the presence of trifluoro-
acetic acid in tetrahydrofuran under reflux, yield 2-(3-ox-
opyrazol-4-yl)malonates 5a,b (Scheme 2, path c).9 In
acidic medium, the reaction proceeds by means of an in-
tramolecular nucleophilic attack of the terminal nitrogen
atom of hydrazones 2a–c to the ester group in the posi-
tion derived from 1,2-diazabuta-1,3-diene, with loss of an
alcohol molecule.10 This event is ascribable to the stron-
ger nucleophilic character of the terminal nitrogen atom
due to the absence of electron-withdrawing group. In fact,
hydrazones obtained from 1-aminocarbonyl or 1-alkoxy-
carbonyl-1,2-diazabuta-1,3-dienes do not exhibit this re-
action. Yields and reaction times for the preparation of
5a,b are given in Table 4.
This procedure represents the first example in literature in
which, even if the cyclization on the carbonyl group de-
rived from dimethyl malonate to give pyrrolones is possi-
ble, as previously described by some of us,6 the annulation
occurs on the ester group derived from 1,2-diazabuta-1,3-
dienes to give pyrazolone derivatives.
2-(3-Oxopyrazol-4-yl)malonates 5a,b are significant in
the synthetic point of view: in fact they are susceptible for
a further 1,4-addition of another molecule of 1,2-diazabu-
ta-1,3-diene 6a,b in tetrahydrofuran in the presence of so-
dium methoxide to give 3-hydrazono-1-(5-oxopyrazol-4-
yl)butanes 7a,b (Scheme 3).
These products are obtained as diastereoisomeric mix-
tures and used as such for the subsequent cyclization. 1H
and 13C NMR spectra of 7a,b show that they exist exclu-
sively in ‘CH’ tautomeric form while the starting 5a,b are
in ‘NH’ tautomeric form. In fact, in 1H NMR spectra, the
H–D-exchange experiments revealed the presence of two
groups of peaks ascribable to ureidic ‘NH’ and/or ‘NH2’
of two diastereoisomers of 7a,b. On the other hand, 90°
DEPT experiments of the same 7a,b shown four signals
attributable to both ‘CH’ groups of the diastereoisomer
mixtures. Yields and reaction times for the preparation of
7a,b are listed in Table 5.
Scheme 2
Synthesis 2002, No. 11, 1546–1552 ISSN 0039-7881 © Thieme Stuttgart · New York

1548
O. A. Attanasi et al.
PAPER
Table 3 Yields and Reaction Times Required for 1-Arylpyrazoles 4a–c
Starting
Material
R1
R2
Product
Reaction
Time (h)a
Yieldb
(%)
Reaction
Time (h)c
Yieldd
(%)
2a
2b
2c
Me
Et
H
4a
4b
4c
7.0
6.5
7.0
47
53
56
19
23
20
41
44
41
H
Me
Cl
a Reaction times using CuCl2 as catalyst.
b Yields of pure isolated products based on 2a–c, using CuCl2 as catalyst.
c Reaction times using Cu(OTf)2 as catalyst.
d Yields of pure isolated products based on 2a–c, using Cu(OTf)2 as catalyst.
Table 4 Yields and Reaction Times Required for 2-(3-Oxopyrazol-
4-yl)malonates 5a,b
Starting
Material
R1
R2
Product Reaction Yielda
Time (h) (%)
2a
2b
2c
Me
Et
H
5a
5a
5b
6
6
6
64
78
81
H
Me
Cl
a Yield of pure isolated products based on 2a–c.
Compounds 7a,b can be easily converted into the relative
4-(2-oxopyrrol-3-yl)pyrazol-3-ones 8a,b using stoichio-
metric amount of sodium methoxide in methanol, by
means of a second five-membered ring closure as de-
scribed above for the formation of 3a–c (Scheme 3). Also
in this case, 8a,b are obtained as diastereoisomeric mix-
tures (50:50) and ‘CH’ tautomeric form is observed, as re-
vealed by 1H-D–H-exchange experiments and 90° DEPT
spectra of these latter compounds. Probably, products 7
and 8 are more sterically congested with respect to the
starting compounds 5, and therefore they adopt the less
hindered ‘CH’ form, allowing the bulky substituent to lie
away from the plane of the pyrazole ring. Yields and reac-
tion times of 8a,b are shown in Table 6.
Scheme 3
Table 6 Yields and Reaction Times Required for 4-(2-Oxopyrrol-
3-yl)pyrazol-3-ones 8a,b
Starting R2
Material
R3
Product
Reaction Yielda
Time (h) (%)
In conclusion, this work describes the importance of the
substituent on the terminal nitrogen atom of the azo-ene
system and offers simple and convenient access to pyrrol-
2-ones,11 1-arylpyrazoles12 and pyrazol-5-ones,3,12 which
are of great interest both as products and intermediates in
organic,3,5,13–15 biological,16 pharmaceutical,17 analytical18
and agricultural19 chemistry.
7a
7b
H
H
8a
8b
6
6
83
71
Cl
Ph
a Yield of pure isolated products based on 7a,b.
Methyl 2-chloroacetoacetate, ethyl 2-chloroacetoacetate, phenylhy-
drazine, 4-chlorophenylhydrazine sulphate, dimethyl malonate,
NaOMe, trifluoroacetic acid, CuCl2, copper(II) trifluoromethane-
sulphonate are commercial materials and were used without further
purification. Solvents were purchased and were used without fur-
ther purification with the exception of THF which was distilled
from NaOH. 1-Aryl-1,2-diazabuta-1,3-dienes 1a–c were prepared
following the typical procedure reported in literature.7 1,2-Diazab-
uta-1,3-dienes 6a,b were synthesized as standard E/Z isomeric mix-
ture according to previously reported procedure.20,21 Petroleum
ether used had bp 40–60 °C.
Table 5 Yields and Reaction Times Required for 3-Hydrazono-1-
(5-oxopyrazol-4-yl)butanes 7a,b
Starting Materials
Product Reaction
Time (h)
Yielda
(%)
5
R2
6
R3
H
5a
5b
H
6a
6b
7a
7b
0.5
0.5
75
68
Cl
Ph
a Yield of pure isolated products.
Synthesis 2002, No. 11, 1546–1552 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Pyrrol-2-ones, 1-Arylpyrazoles, 2-(3-Oxopyrazol-4-yl)malonates and 4-(2-Oxopyrrol-3-yl)pyrazol-3-ones
1549
Melting points were determined in open capillary tubes and are un-
corrected. IR-FT spectra were obtained as Nujol mulls. Mass spec-
Anal. Calcd for C17H22N2O6 (350.38): C, 58.28; H, 6.33; N, 8.00.
Found: C, 58.41; H, 6.28; N, 8.18.
tra were made at an ionizing voltage of 70 eV. All 1H NMR and 13
C
NMR spectra were recorded at 400 and 100.56 MHz, respectively.
Chemical shifts ( H) are reported relative to TMS as internal stan-
dard. All coupling constants (J) values are given in Hz. Chemical
shifts ( C) are reported relative to DMSO-d6 or CDCl3 as internal
standard in a broad band decoupled mode; the multiplicities were
obtained using 135 and 90° DEPT experiments to aid in assignment
(q = methyl, t = methylene, d = methine, s = quaternary). The ab-
breviations used are as follows: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad; all the NH and OH exchanged with
D2O. NOE enhancement factors were determined in degassed
CDCl3 0.01 M solution at 300 K, using NOEDIF pulse program of
Varian. Irradiation time was 4 sec, with power level of 10. Precoat-
ed silica gel plates 0.25 mm were employed for analytical TLC and
silica gel 35–70 m for column chromatography. All new com-
pounds showed satisfactory elemental analysis (C 0.35; H 0.30;
N 0.30).
Trimethyl (E)-3-[2-(4-Chlorophenyl)hydrazono]butane-1,1,2-
tricarboxylate (2c)
Yield: 189 mg (51%); white powder (EtOAc–petroleum ether); mp
139–140 °C.
IR (Nujol): 3324, 1751, 1719 cm–1.
1H NMR (400 MHz, CDCl3): = 1.97 (s, 3 H, CH3), 3.66 (s, 3 H,
OCH3), 3.70 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3), 4.11 (d, J = 11.2
Hz, 1 H, CH), 4.40 (d, J = 11.2 Hz, 1 H, CH), 6.93 (d, J = 8.8 Hz, 2
Harom), 7.10 (br s, 1 H, NH), 7.16 (d, J = 8.8 Hz, 2 Harom).
13C NMR (100.56 MHz, CDCl3): = 15.10 (q), 52.04 (d), 53.04 (q),
53.15 (q), 53.36 (q), 53.42 (d), 114.19 (d), 124.92 (s), 129.20 (d),
139.32 (s), 143.64 (s), 168.27 (s), 168.47 (s), 170.55 (s).
MS: m/z (%) = 372 (M+ + 2, 38), 370 (M+, 48), 340 (11), 338 (33),
308 (16), 306 (49), 281 (33), 279 (100).
Anal. Calcd for C16H19ClN2O6 (370.74): C, 51.83; H, 5.16; N, 7.56.
Found: C, 51.92; H, 5.11; N, 7.71.
Hydrazones 2a–c; General Procedure
To a magnetically stirred solution of dimethyl malonate (132.12
mg, 1 mmol) and NaOMe (27.01 mg, 0.5 mmol) in THF (5 mL), a
solution of the 1-aryl-1,2-diazabuta-1,3-dienes 1a–c (1 mmol) in
THF (5 mL) was added. The reaction was allowed to stand at r.t. un-
til the complete disappearance of the reagents (47–54 h, monitored
by TLC). The solvent was evaporated under reduced pressure and
products 2a–c were purified by chromatography on a silica gel col-
umn (elution mixture: cyclohexane–EtOAc, 70:30) and then crys-
tallized from EtOAc–petroleum ether.
NOE Enhancement factors: CH3{NH} 16%; NH{CH3} 5%.
Pyrrol-2-ones 3a–c; General Procedure
To a magnetically stirred solution of hydrazones 2a–c (1 mmol) in
MeOH (10 mL) was added NaOMe (16.2 mg, 0.3 mmol). The reac-
tion was allowed to stand at r.t. until the complete disappearance of
3a–c (4.5–5.5 h, monitored by TLC). The solvent was evaporated
under reduced pressure and the products 3a–c were obtained as oils
by chromatography on a silica gel column (elution mixture: cyclo-
hexane–EtOAc, 60:40).
Trimethyl (E)-3-(2-Phenylhydrazono)butane-1,1,2-tricarboxy-
late (2a)
Dimethyl 1-Anilino-2-oxo-2,3-dihydro-1H-pyrrole-3,4-dicar-
boxylate (3a)
Yield: 216 mg (71%); yellow oil.
IR (Nujol): 3317, 1753, 1728, 1713 cm–1.
1H NMR (400 MHz, CDCl3): = 2.44 (s, 3 H, CH3), 3.76 (s, 3 H,
OCH3), 3.79 (s, 3 H, OCH3), 4.30 (s, 1 H, CH), 6.42 (s, 1 H, NH),
6.71 (d, J = 7.6 Hz, 2 Harom), 6.95 (t, J = 7.6 Hz, 1 Harom), 7.21–7.26
(m, 2 Harom).
13C NMR (100.56 MHz, CDCl3): = 11.65 (q), 51.44 (q), 52.02 (d),
53.14 (q), 102.29 (s), 112.90 (d), 122.10 (d), 129.47 (d), 145.57 (s),
157.77 (s), 163.47 (s), 166.17 (s), 170.38 (s).
Yield: 199 mg (59%); white powder (EtOAc–petroleum ether); mp
136–137 °C.
IR (Nujol): 3333, 1747, 1717 cm–1.
1H NMR (400 MHz, CDCl3): = 1.98 (s, 3 H, CH3), 3.67 (s, 3 H,
OCH3), 3.73 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 4.12 (d, J = 11.2
Hz, 1 H, CH), 4.43 (d, J = 11.2 Hz, 1 H, CH), 6.84 (t, J = 8.8 Hz, 1
Harom), 7.01 (d, J = 8.8 Hz, 2 Harom), 7.05–7.26 (m, 3 Harom and NH).
13C NMR (100.56 MHz, CDCl3): = 14.78 (q), 51.98 (d), 52.84 (q),
53.00 (q), 53.17 (q), 53.29 (d), 113.10 (d), 120.44 (d), 129.40 (d),
138.61 (s), 145.14 (s), 168.48 (s), 168.74 (s), 170.85 (s).
MS: m/z (%) = 336 (M+, 60), 304 (29), 272 (68), 245 (100).
MS: m/z (%) = 304 (M+, 29), 272 (100).
Anal. Calcd for C16H20N2O6 (336.35): C, 57.14; H, 5.99; N, 8.33.
Found: C, 57.28; H, 5.79; N, 8.39.
Anal. Calcd for C15H16N2O5 (304.31): C, 59.21; H, 5.30; N, 9.21.
Found: C, 59.03; H, 5.44; N, 9.34.
2-Ethyl 1,1-Dimethyl (E)-3-(2-phenylhydrazono)butane-1,1,2-
tricarboxylate (2b)
Yield: 214 mg (61%); white powder (EtOAc–petroleum ether); mp
141–143 °C.
4-Ethyl 3-Methyl 1-Anilino-2-oxo-2,3-dihydro-1H-pyrrole-3,4-
dicarboxylate (3b)
Yield: 217 mg (68%); yellow oil.
IR (Nujol): 3308, 1741, 1731, 1706 cm–1.
1H NMR (400 MHz, CDCl3): = 1.28 (t, J = 7.2 Hz, 3 H,
OCH2CH3), 2.48 (s, 3 H, CH3), 3.84 (s, 3 H, OCH3), 4.19–4.30 (m,
3 H, CH and OCH2CH3), 6.26 (s, 1 H, NH), 6.75 (d, J = 7.6 Hz, 2
Harom), 6.97 (t, J = 7.6 Hz, 1 Harom), 7.23–7.28 (m, 2 Harom).
13C NMR (100.56 MHz, CDCl3): = 11.50 (q), 13.96 (q), 53.67 (d),
53.72 (q), 60.16 (t), 106.38 (s), 112.68 (d), 122.06 (d), 129.28 (d),
145.25 (s), 160.09 (s), 162.26 (s), 168.55 (s), 171.61 (s).
IR (Nujol): 3317, 1761, 1722 cm–1.
1H NMR (400 MHz, CDCl3): = 1.15 (t, J = 7.2 Hz, 3 H,
OCH2CH3), 1.93 (s, 3 H, CH3), 3.58 (s, 3 H, OCH3), 3.66 (s, 3 H,
OCH3), 3.91 (d, J = 11.2 Hz, 1 H, CH), 4.10 (q, J = 7.2 Hz, 2 H,
OCH2CH3), 4.18 (d, J = 11.2 Hz, 1 H, CH), 6.70 (t, J = 8.6 Hz, 1
Harom), 7.01 (d, J = 8.6 Hz, 2 Harom), 7.06–7.22 (m, 3 Harom and NH).
13C NMR (100.56 MHz, CDCl3): = 14.28 (q), 14.79 (q), 51.96 (d),
52.96 (q), 53.00 (q), 53.14 (d), 61.79 (t), 113.07 (d), 120.36 (d),
129.38 (d), 138.74 (s), 145.22 (s), 168.55 (s), 168.74 (s), 170.28 (s).
MS: m/z (%) = 318 (M+, 25), 287 (16), 242 (100).
MS: m/z (%) = 350 (M+, 38), 304 (43), 272 (50), 259 (18), 245
(100).
Anal. Calcd for C16H18N2O5 (318.33): C, 60.37; H, 5.70; N, 8.80.
Found: C, 60.44; H, 5.78; N, 8.91.
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O. A. Attanasi et al.
PAPER
Dimethyl 1-(4-Chloroanilino)-2-oxo-2,3-dihydro-1H-pyrrole-
3,4-dicarboxylate (3c)
Yield: 254 mg (75%); yellow oil.
13C NMR (100.56 MHz, CDCl3): = 13.67 (q), 52.06 (q), 53.67 (q),
115.93 (s), 125.22 (d), 129.76 (d), 134.90 (s), 137.56 (s), 137.84 (s),
151.69 (s), 161.80 (s), 163.14 (s).
IR (Nujol): 3303, 1741, 1736, 1712 cm–1.
MS: m/z (%) = 310 (M+ + 2, 26), 308 (M+, 77), 279 (33), 277 (100).
1H NMR (400 MHz, CDCl3): = 2.44 (s, 3 H, CH3), 3.77 (s, 3 H,
OCH3), 3.80 (s, 3 H, OCH3), 4.30 (s, 1 H, CH), 6.28 (s, 1 H, NH),
6.66 (d, J = 8.4 Hz, 2 Harom), 7.21 (d, J = 8.4 Hz, 2 Harom).
Anal. Calcd for C14H13ClN2O4 (308.72): C, 54.47; H, 4.24; N, 9.07.
Found: C, 54.39; H, 4.38; N, 9.21.
2-(3-Oxopyrazol-4-yl)malonates 5a,b; General Procedure
A solution of the hydrazone 2a–c (1 mmol) in THF (10 mL) was re-
fluxed with trifluoroacetic acid (0.8 mL) for 6 h until the disappear-
ance of 2a–c (monitored by TLC). The mixture was neutralized by
addition of NaHCO3 until pH 7 and filtered. The solvent was evap-
orated under reduced pressure and products 5a,b were purified by
chromatography on a silica gel column (elution mixture: cyclohex-
ane–EtOAc, 40:60) and then crystallized from EtOAc–petroleum
ether.
13C NMR (100.56 MHz, CDCl3): = 11.92 (q), 51.82 (q), 52.26 (d),
53.52 (q), 102.87 (s), 114.57 (d), 127.55 (s), 129.78 (d), 144.42 (s),
157.47 (s), 163.64 (s), 166.32 (s), 170.52 (s).
MS: m/z (%) = 340 (M+ + 2, 9), 338 (M+, 27), 308 (33), 306 (100).
Anal. Calcd for C15H15ClN2O5 (338.75): C, 53.19; H, 4.46; N, 8.27.
Found: C, 53.29; H, 4.33; N, 8.41.
1-Arylpyrazoles 4a–c; General Procedure
To a magnetically stirred solution of the hydrazone 2a–c (1 mmol)
in THF (10 mL) was added CuCl2 (134.35 mg, 1.0 mmol) or
Cu(OTf)2 (361.68 mg, 1.0 mmol). The reaction was allowed to
stand at r.t. until the complete disappearance of 2a–c (6.5–23.0 h,
monitored by TLC). The solvent was evaporated under reduced
pressure and the products 4a–c were obtained as oils by chromatog-
raphy on a silica gel column (elution mixture: cyclohexane–EtOAc,
80:20).
Dimethyl 2-(5-Methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-
4-yl)malonate (5a)
Yield: 195 mg (64%) from 2a, 237 mg (78%) from 2b; white pow-
der (EtOAc–petroleum ether); mp 64–66 °C.
IR (Nujol): 3224, 1742, 1690, 1602 cm–1.
1H NMR (400 MHz, CDCl3): = 2.08 (s, 3 H, CH3), 3.65 (s, 6 H, 2
OCH3), 4.54 (s, 1 H, CH), 7.06–7.18 (m, 3 Harom), 7.39 (d, J = 7.6
Hz, 2 Harom), 10.74 (br s, 1 H, NH).
13C NMR (100.56 MHz, CDCl3): = 25.74 (q), 46.54 (d), 52.98 (q),
96.61 (s), 119.93 (s), 121.30 (d), 126.30 (d), 128.96 (d), 136.22 (s),
147.90 (s), 169.05 (s).
Dimethyl 3-Methyl-1-phenyl-1H-pyrazole-4,5-dicarboxylate
(4a)
Yield: 129 mg (47%) using CuCl2, 113 mg (41%) using Cu(OTf)2;
yellow oil.
IR (Nujol): 1777, 1714 cm–1.
MS: m/z (%) = 304 (M+, 63), 272 (21), 245 (100).
1H NMR (400 MHz, CDCl3): = 2.52 (s, 3 H, CH3), 3.85 (s, 6 H, 2
OCH3), 7.44-7.49 (m, 5 Harom).
Anal. Calcd for C15H16N2O5 (304.31): C, 59.21; H, 5.30; N, 9.21.
Found: C, 59.03; H, 5.44; N, 9.41.
13C NMR (100.56 MHz, CDCl3): = 13.69 (q), 51.97 (q), 53.53 (q),
113.37 (s), 123.95 (d), 129.02 (d), 129.57 (d), 137.91 (s), 139.08 (s),
151.44 (s), 161.98 (s), 163.27 (s).
Dimethyl 2-[2-(4-Chlorophenyl)-5-methyl-3-oxo-2,3-dihydro-
1H-pyrazol-4-yl]malonate (5b)
Yield: 274 mg (81%); white powder (EtOAc–petroleum ether); mp
75–77 °C.
MS: m/z (%) = 274 (M+, 45), 242 (100).
IR (Nujol): 3228, 1740, 1695, 1600 cm–1.
Anal. Calcd for C14H14N2O4 (274.28): C, 61.31; H, 5.14; N, 10.21.
Found: C, 61.50; H, 5.21; N, 10.09.
1H NMR (400 MHz, CDCl3): = 2.15 (s, 3 H, CH3), 3.71 (s, 6 H, 2
OCH3), 4.54 (s, 1 H, CH), 7.17 (d, J = 8.8 Hz, 2 Harom), 7.41 (d,
J = 8.8 Hz, 2 Harom), 9.40 (br s, 1 H, NH).
13C NMR (100.56 MHz, CDCl3): = 26.78 (q), 46.51 (d), 53.00 (q),
95.66 (s), 119.89 (s), 122.14 (d), 128.78 (d), 131.47 (s), 134.74 (s),
148.19 (s), 168.84 (s).
4-Ethyl 5-Methyl 3-Methyl-1-phenyl-1H-pyrazole-4,5-dicar-
boxylate (4b)
Yield: 153 mg (53%) using CuCl2, 127 mg (44%) using Cu(OTf)2;
yellow oil.
IR (Nujol): 1751, 1712 cm–1.
1H NMR (400 MHz, CDCl3): = 1.34 (t, J = 7.2 Hz, 3 H,
OCH2CH3), 2.53 (s, 3 H, CH3), 3.85 (s, 3 H, OCH3), 4.30 (q, J = 7.2
Hz, 2 H, OCH2CH3), 7.41–7.50 (m, 5 Harom).
MS: m/z (%) = 340 (M+ + 2, 15), 338 (M+, 45), 281 (33), 279 (100).
Anal. Calcd for C15H15ClN2O5 (338.75): C, 53.19; H, 4.46; N, 8.27.
Found: C, 53.33; H, 4.51; N, 8.11.
13C NMR (100.56 MHz, CDCl3): = 13.68 (q), 14.44 (q), 53.45 (q),
60.81 (t), 113.53 (s), 123.94 (d), 129.00 (d), 129.58 (d), 137.79 (s),
139.09 (s), 151.50 (s), 162.07 (s), 162.80 (s).
3-Hydrazono-1-(5-oxopyrazol-4-yl)butanes 7a,b; General Pro-
cedure
To a magnetically stirred solution of 5a,b (1 mmol) and NaOMe
(27.01 mg, 0.5 mmol) in THF (5 mL) was added a solution of 6a,b
(1.0 mmol) in THF (5 mL). The reaction was allowed to stand at r.t.
for 0.5 h until the complete disappearance of the reagents (moni-
tored by TLC). The solvent was evaporated under reduced pressure
and the products 7a,b were purified by chromatography on a silica
gel column (elution mixture: cyclohexane–EtOAc, 70:30) and then
crystallized from EtOAc–petroleum ether.
MS: m/z (%) = 288 (M+, 36), 242 (100).
Anal. Calcd for C15H16N2O4 (288.31): C, 62.49; H, 5.59; N, 9.72.
Found: C, 62.40; H, 5.48; N, 9.79.
Dimethyl 1-(4-Chlorophenyl)-3-methyl-1H-pyrazole-4,5-dicar-
boxylate (4c)
Yield: 173 mg (56%) using CuCl2, 127 mg (41%) using Cu(OTf)2;
yellow oil.
1,1-Dimethyl 2-Ethyl 3-[2-(Aminocarbonyl)hydrazono]-1-(3-
methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)butane-
1,1,2-tricarboxylate (7a)
Yield: 367 mg (75%); white powder (EtOAc–petroleum ether); mp
177–179 °C.
IR (Nujol): 1732, 1716 cm–1.
1H NMR (400 MHz, CDCl3): = 2.51 (s, 3 H, CH3), 3.85 (s, 3 H,
OCH3), 3.87 (s, 3 H, OCH3), 7.42 (s, 4 Harom).
Synthesis 2002, No. 11, 1546–1552 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Pyrrol-2-ones, 1-Arylpyrazoles, 2-(3-Oxopyrazol-4-yl)malonates and 4-(2-Oxopyrrol-3-yl)pyrazol-3-ones
1551
IR (Nujol): 3558, 3435, 3221, 3132, 1766, 1737, 1712, 1678, 1561
cm–1.
s, 1 H, CH), 6.40 (br s, 2 H, NH2), 7.18–7.40 (m, 1 Harom), 7.39–7.47
(m, 2 Harom), 7.66–7.73 (m, 2 Harom), 8.81 (br s, 1 H, NH).
1H NMR (400 MHz, DMSO-d6):
= 1.13–1.17 (m, 3 H,
13C NMR (100.56 MHz, DMSO-d6): = 14.32 (q), 14.43 (q), 15.54
(q), 16.03 (q), 16.19 (q), 16.34 (q), 52.17 (d), 52.34 (d), 53.17 (q),
53.26 (q), 53.52 (s), 53.65 (s), 61.52 (t), 61.58 (t), 102.03 (s), 102.37
(s), 118.84 (d), 119.07 (d), 125.45 (d), 125.60 (d), 129.49 (d),
129.60 (d), 138.15 (s), 138.27 (s), 157.94 (s), 158.74 (s), 158.87 (s),
159.62 (s), 163.33 (s), 163.47 (s), 163.80 (s), 164.96 (s), 165.37 (s),
165.83 (s), 166.11 (s), 166.24 (s), 172.65 (s), 172.88 (s).
OCH2CH3), 1.76 and 1.77 (2 s, 3 H, CH3), 2.19 and 2.21 (2 s, 3 H,
CH3), 3.58 and 3.63 (2 s, 3 H, OCH3), 3.65 and 3.69 (2 s, 3 H,
OCH3), 4.11–4.18 (m, 3 H, OCH2CH3 and CH), 4.46 and 4.48 (2 s,
1 H, CH), 6.21 (br s, 2 H, NH2), 7.19–7.24 (m, 1 Harom), 7.41–7.44
(m, 2 Harom), 7.65–7.68 (m, 2 Harom), 9.34 and 9.36 (s, 1 H, NH).
13C NMR (100.56 MHz, DMSO-d6): = 13.79 (q), 13.85 (q), 16.50
(q), 16.52 (q), 16.96 (q), 16.97 (q), 51.99 (d), 52.00 (d), 52.97 (q),
53.00 (q), 53.08 (q), 53.10 (q), 55.53 (d), 55.57 (d), 57.40 (s), 57.48
(s), 61.40 (t), 61.42 (t), 118.56 (d), 118.59 (d), 125.12 (d), 125.13
(d), 128.68 (d), 136.93 (s), 136.96 (s), 140.05 (s), 140.07 (s), 156.25
(s), 156.26 (s), 158.53 (s), 158.55 (s), 165.60 (s), 165.90 (s), 168.30
(s), 168.32 (s), 171.06 (s), 171.10 (s).
MS: m/z (%) = 458 (M+ + 1, 21), 457 (M+, 59), 414 (55), 398 (10),
355 (20), 309 (68), 205 (100).
Anal. Calcd for C21H23N5O7 (457.45): C, 55.14; H, 5.07; N, 15.31.
Found: C, 55.21; H, 5.00; N, 15.51.
4-Ethyl 3-Methyl 1-[(Anilinocarbonyl)amino]-5-methyl-3-[3-
methyl-5-oxo-1-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-4-
yl]-2-oxo-2,3-dihydro-1H-pyrrole-3,4-dicarboxylate (8b)
Yield: 403 mg (71%); white powder (EtOAc–petroleum ether); mp
161–166 °C.
MS: m/z (%) = 490 (M+ + 1, 19), 489 (M+, 78), 444 (9), 430 (25),
400 (22), 341 (69), 304 (100).
Anal. Calcd for C22H27N5O8 (489.49): C, 53.98; H, 5.56; N, 14.31.
Found: C, 53.81; H, 5.44; N, 14.38.
IR (Nujol): 3458, 3340, 1749, 1710, 1698, 1665, 1595 cm–1.
1,1-Dimethyl 2-Ethyl 3-[2-(Anilinocarbonyl)hydrazono]-1-[1-
(4-chlorophenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-
yl]butane-1,1,2-tricarboxylate (7b)
Yield: 408 mg (68%); white powder (EtOAc–petroleum ether); mp
186–188 °C.
1H NMR (400 MHz, DMSO-d6):
= 1.03–1.11 (m, 3 H,
OCH2CH3), 1.96 and 2.00 (2 s, 3 H, CH3), 2.23 and 2.26 (2 s, 3 H,
CH3), 3.56 and 3.58 (2 s, 3 H, OCH3), 4.02–4.18 (m, 2 H,
OCH2CH3), 5.11 (br s, 1 H, CH), 7.05–7.36 (m, 5 Harom), 7.48–7.57
(m, 2 Harom), 7.70–7.79 (m, 2 Harom), 8.36 (br s, 1 H, NH), 9.44 (br
s, 1 H, NH).
IR (Nujol): 3564, 3240, 3116, 1774, 1741, 1702, 1668, 1559 cm–1.
1H NMR (400 MHz, CDCl3): = 1.23–1.30 (m, 3 H, OCH2CH3),
1.97 and 1.98 (2 s, 3 H, CH3), 2.34 and 2.35 (2 s, 3 H, CH3), 3.66
and 3.68 (2 s, 3 H, OCH3), 3.76 and 3.80 (2 s, 3 H, OCH3), 4.19–
4.24 (m, 2 H, OCH2CH3), 4.41 and 4.44 (2 s, 1 H, CH), 4.63 and
4.66 (2 s, 1 H, CH), 7.05–7.33 (m, 5 Harom), 7.47–7.73 (m, 4 Harom),
8.30 and 8.32 (2 s, 1 H, NH), 9.30 and 9.35 (2 s, 1 H, NH).
13C NMR (100.56 MHz, CDCl3): = 13.93 (q), 13.99 (q), 16.70 (q),
16.73 (q), 26.84 (q), 26.88 (q), 52.40 (d), 52.96 (d), 53.09 (q), 53.27
(q), 53.32 (q), 55.50 (d), 55.70 (d), 57.75 (s), 57.92 (s), 62.09 (t),
62.24 (t), 119.01 (d), 119.83 (d), 120.06 (d), 120.21 (d), 123.18 (d),
123.37 (d), 128.50 (d), 128.85 (d), 130.53 (s), 130.61 (s), 135.79 (s),
135.86 (s), 137.91 (s), 138.05 (s), 141.76 (s), 141.91 (s), 153.64 (s),
159.24 (s), 159.40 (s), 166.29 (s), 166.66 (s), 166.70 (s), 166.81 (s),
168.71 (s), 171.80 (s).
13C NMR (100.56 MHz, DMSO-d6): = 14.34 (q), 14.47 (q), 15.54
(q), 15.99 (q), 16.23 (q), 16.40 (q), 52.22 (d), 52.43 (d), 53.19 (q),
53.32 (q), 53.57 (s), 53.68 (s), 61.55 (t), 61.59 (t), 102.07 (s), 102.38
(s), 119.01 (d), 119.09 (d), 120.03 (d), 120.11 (d), 120.22 (d),
120.43 (d), 123.18 (d), 123.33 (d), 128.86 (d), 129.01 (d), 130.41
(s), 130.55 (s), 135.79 (s), 135.81 (s), 138.11 (s), 138.21 (s), 158.00
(s), 158.69 (s), 158.99 (s), 159.51 (s), 163.31 (s), 163.49 (s), 163.91
(s), 164.93 (s), 165.40 (s), 165.91 (s), 166.13 (s), 166.27 (s), 172.69
(s), 172.91 (s).
MS: m/z (%) = 569 (M+ + 2, 11), 568 (M+ + 1, 8), 567 (M+, 33), 450
(33), 448 (100).
Anal. Calcd for C27H26ClN5O7 (567.99): C, 57.10; H, 4.61; N,
12.33. Found: C, 57.21; H, 4.68; N, 12.28.
MS: m/z (%) = 601 (M+ + 2, 11), 599 (M+, 33), 508 (33), 506 (100).
Acknowledgement
Anal. Calcd for C28H30ClN5O8 (600.03): C, 56.05; H, 5.04; N,
11.67. Found: C, 56.11; H, 5.12; N, 11.58.
This work was supported by financial assistance from the Ministero
dell'Università
e della Ricerca Scientifica e Tecnologica
4-(2-Oxopyrrol-3-yl)pyrazol-3-ones 8a,b; General Procedure
To a magnetically stirred solution of 7a,b (1 mmol) in MeOH (10
mL) was added NaOMe (54.02 mg, 1.0 mmol). The reaction was al-
lowed to stand at r.t. for 6.0 h until the complete disappearance of
7a,b (monitored by TLC). The solvent was evaporated under re-
duced pressure and the products 8a,b were purified by chromatog-
raphy on a silica gel column (elution mixture: cyclohexane–EtOAc,
70:30) and then crystallized from EtOAc–petroleum ether.
(M.U.R.S.T.-Roma-National Project Building-blocks da e/o per si-
sterai eterociclici. Processi innovativi e sintesi di molecole di poten-
ziale attività biologica), the Consiglio Nazionale delle Ricerche (C.
N. R.-Roma) and the Università degli Studi di Urbino.
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Synthesis 2002, No. 11, 1546–1552 ISSN 0039-7881 © Thieme Stuttgart · New York

1552
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