Regioselective role of the hydrazide moiety in the formation of complex pyrrole-pyrazole systems

Article abstract of DOI:10.1016/S0040-4020(00)01125-X

The treatment of alkyl 2-chloroacetoacetate with ethyl 3-hydrazino-3-oxopropionate, (4-chlorobenzenesulphonyl)acetic acid hydrazide, 4-nitrophenylacetic acid hydrazide, phenylacetic acid hydrazide, thiophene-3-acetic acid hydrazide or indole-3-acetic acid hydrazide leads to the corresponding hydrazone derivatives. In the presence of sodium carbonate, these compounds react at room temperature with acetoacetanilide or 2,4-pentanedione to give the corresponding 1-aminopyrrole rings through the relevant 1,2-diaza-1,3-butadiene intermediates. In the presence of sodium methoxide, the activated methylene group present on the 1-amino side chain of the heterocycles obtained from ethyl 3-hydrazino-3-oxopropionate or 4-nitrophenylacetic acid hydrazide attacks at room temperature 1,2-diaza-1,3-butadienes affording the respective hydrazonic 1,4-adducts. Under basic conditions, these adducts cyclise at room temperature providing-NH-CO-CH-bridged pyrrole-pyrazole systems. In the case of (4-chlorobenzenesulphonyl)acetic acid hydrazide, the corresponding 1-aminopyrrole does not add a further molecule of 1,2-diaza-1,3-butadiene giving rise to 1H-pyrrole and 2-oxohydrazone derivatives as identified compounds. Under the same reaction conditions, the NH group of 1-aminopyrroles derived from phenylacetic acid hydrazide, thiophene-3-acetic acid hydrazide or indole-3-acetic acid hydrazide adds at room temperature 1,2-diaza-1,3-butadienes producing another type of hydrazonic 1,4-adduct. Under basic conditions, these adducts cyclise at room temperature giving rise to different N-bonded pyrrole-pyrazole systems.

Full text of DOI:10.1016/S0040-4020(00)01125-X

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1387±1394
Regioselective role of the hydrazide moiety in the formation of
complex pyrrole±pyrazole systems
Orazio A. Attanasi, Paolino Filippone,p Francesca R. Perrulli and Stefania Santeusanio
Á
Istituto di Chimica Organica, Universita di Urbino, Piazza della Repubblica 13, 61029 Urbino, Italy
Received 21 July 2000; revised 8 November 2000; accepted 23 November 2000
AbstractÐThe treatment of alkyl 2-chloroacetoacetate with ethyl 3-hydrazino-3-oxopropionate, (4-chlorobenzenesulphonyl)acetic acid
hydrazide, 4-nitrophenylacetic acid hydrazide, phenylacetic acid hydrazide, thiophene-3-acetic acid hydrazide or indole-3-acetic acid
hydrazide leads to the corresponding hydrazone derivatives. In the presence of sodium carbonate, these compounds react at room temperature
with acetoacetanilide or 2,4-pentanedione to give the corresponding 1-aminopyrrole rings through the relevant 1,2-diaza-1,3-butadiene
intermediates. In the presence of sodium methoxide, the activated methylene group present on the 1-amino side chain of the heterocycles
obtained from ethyl 3-hydrazino-3-oxopropionate or 4-nitrophenylacetic acid hydrazide attacks at room temperature 1,2-diaza-1,3-buta-
dienes affording the respective hydrazonic 1,4-adducts. Under basic conditions, these adducts cyclise at room temperature providing
ZNHZCOZCH-bridged pyrrole±pyrazole systems. In the case of (4-chlorobenzenesulphonyl)acetic acid hydrazide, the corresponding
1-aminopyrrole does not add a further molecule of 1,2-diaza-1,3-butadiene giving rise to 1H-pyrrole and 2-oxohydrazone derivatives as
identi®ed compounds. Under the same reaction conditions, the NH group of 1-aminopyrroles derived from phenylacetic acid hydrazide,
thiophene-3-acetic acid hydrazide or indole-3-acetic acid hydrazide adds at room temperature 1,2-diaza-1,3-butadienes producing another
type of hydrazonic 1,4-adduct. Under basic conditions, these adducts cyclise at room temperature giving rise to different N-bonded pyrrole±
pyrazole systems. q 2001 Published by Elsevier Science Ltd.
1. Introduction
mented.1±6 In a previous preliminary paper, we reported the
sequential construction of widely functionalized pyrrole±
pyrrole or pyrrole±pyrazole systems from conjugated
azoalkenes.7 In that report, we described an easy protocol
The synthetic usefulness of 1,2-diaza-1,3-butadienes as
building blocks in organic chemistry has been well docu-
Scheme 1.
Keywords: hydrazides; hydrazones; 1,2-diaza-1,3-butadienes; pyrroles; pyrazoles.
Corresponding author. Fax: 139-0722-2907; e-mail: attanasi@uniurb.it
p
0040±4020/01/$ - see front matter q 2001 Published by Elsevier Science Ltd.
PII: S0040-4020(00)01125-X

1388
O. A. Attanasi et al. / Tetrahedron 57 (2001) 1387±1394
Table 1. Yield and reaction time of pyrroles (5a±g), 1,4-adducts (7a±i) and pyrrolo-pyrazoles (8a±i)
5
Yielda (%)
Reaction time (h)
M.p.b (8C)
7
Yielda (%)
Reaction time (h)
8
Yielda (%)
Reaction time (h)
a
b
c
d
e
f
70
51
88
49
83
64
69
20
18
26
16
12
24
26
175±177
90±92
a
b
c
d
e
f
g
h
i
60
66
86
62
72
71
60
70
67
48
36
24
38
a
b
c
d
e
f
g
h
i
62
67
64
51
46
67
38
48
45
36
48
24
48
24
32
24
6
204±206
161±165
100±102
114±115
165±166
40
108
112
38
g
120
9
a
Yield of pure isolated products.
Melting points are uncorrected.
b
Scheme 2.

O. A. Attanasi et al. / Tetrahedron 57 (2001) 1387±1394
1389
Scheme 3.
for the synthesis of 1-aminopyrroles bearing an activated
methylene group on the N-amino side chain. These deriva-
tives were used as C-nucleophiles towards 1,2-diaza-1,3-
butadienes affording 1,4-hydrazone derivatives that in turn
were subjected to a further intramolecular pyrrole or pyra-
zole closure in which the key role was played by the cyano
or carboxylate group, respectively.
The methylene group of the 1-amino side chain of the
pyrrole ring directly activated by an ethylcarboxylate
group (5a±b) or remotely activated by a 4-nitrophenyl
group as in derivative 5d under basic conditions in THF at
room temperature attacks the C-4 of 1,2-diaza-1,3-
butadienes 6a±d affording the corresponding hydrazone
C-adducts 7a±e as diastereomeric mixtures. Cyclisation of
these last derivatives in the presence of freshly generated
sodium methoxide in THF/MeOH mixture at room tempera-
ture provides ZNHZCOZCH-bridged pyrrole±pyrazole
systems 8a±e (Scheme 2 and Table 1). The multiple signals
at d 1.9±2.3 ppm observed in the 1H NMR spectra of 8a±e
are attributable to a rotameric effect. In the DNMR experi-
ments carried out in DMSO-d6 (293±360 K) they simplify
in the expected signals.
2. Results and discussion
Herein, we report two different types of pyrrole±pyrazole
systems arising by means of C- or N-bond formation as a
consequence of the different substituents present on the
hydrazide moiety. In fact, the treatment of methyl 2-chloro-
acetoacetate (1a) or ethyl 2-chloroacetoacetate (1b) with
ethyl 3-hydrazino-3-oxopropionate (2a), (4-chlorobenzene-
sulphonyl)acetic acid hydrazide (2b), 4-nitrophenylacetic
acid hydrazide (2c), phenylacetic acid hydrazide (2d), thio-
phene-3-acetic acid hydrazide (2e) or indole-3-acetic acid
hydrazide (2f) in THF at room temperature leads to the
corresponding a-chlorohydrazone derivatives 3a±f.8,9 In
the presence of sodium carbonate, these latter compounds
react in THF at room temperature with acetoacetanilide (4a)
or 2,4-pentanedione (4b) to give the relevant 1-aminopyr-
role rings 5a±g in good to excellent yields (Scheme 1 and
Table 1).
In the case of the 4-chlorobenzensulphonyl derivative (5c)
the reaction with 6a under the same reaction conditions was
also incomplete after several days, giving a complex crude
mixture. Unreacted pyrrole derivative with poor amounts of
1H-pyrrole 9 and 2-oxohydrazone 1010 as degradative and/
or oxidative by-products are recovered instead of the
expected C-adduct 7, in accordance with our previous ®nd-
ings on analogous compounds (Scheme 3).6b,j
Pyrrole derivatives 5e±g bearing phenyl, thienyl or indolyl
residue contain a less activated methylene group on the
N-amino side chain and produce conjugated adducts 7f±i
by means of N-amino attack at the azo-ene system of
6c,e±g. The pyrazole annulation performed under the
same reaction conditions affords ZN-bridged pyrrole±
pyrazole systems 8f±i as mixtures of conformers. In fact
1H NMR spectra show diastereotopic protons of the
COCH2R2 group at d 3.63±4.06 ppm (Scheme 2 and
Table 1). By DNMR studies carried out in DMSO-d6
(293±340 K) their multiplicity disappears to give a singlet.
Both pyrazole ring closures involve the amino nitrogen
atom (sCvNZNHZ) of the 1,4-adducts 7a±i and the
This latter reaction probably occurs via the formation in situ
of the conjugated azoalkene intermediate, as shown by the
appearance of the typical orange or red colour of such a
compound due to the base-promoted dehydrohalogenation
of the corresponding a-chlorohydrazone derivative. The
subsequent fading of the colour of the reaction mixture
occurs when the compound loses the conjugated double
bonds by addition of the b-dicarbonyl compound. This
hypothesis is also supported by previous analogous
®ndings.7,9

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O. A. Attanasi et al. / Tetrahedron 57 (2001) 1387±1394
carboxylate group at the carbon in position 4 of the 1,2-
diaza-1,3-butadiene molecule 6a±g with loss of an alcohol
molecule (Scheme 2 and Table 1).
(1.0 mmol) or 1,3-pentanedione 4b (1.0 mmol) and
anhydrous sodium carbonate (1.5 mmol) in THF (10 ml).
The reaction mixture was allowed to stand at room tempera-
ture until the complete disappearance of a-chlorohydrazone
3a±f (12±26 h, monitored by TLC). The reaction solvent
was evaporated under reduced pressure, the residue
suspended in ethyl acetate and washed in a separatory
funnel with 2N HCl (until pH 2) and then with water. The
organic layer was dried over anhydrous Na2SO4 and evapo-
rated in vacuo. The residue afforded pure 1-aminopyrrole
5a±g directly by crystallisation from appropriate solvents
(see below) or after chromatographic puri®cation on a silica
gel column, eluting with cyclohexane±ethyl acetate
mixtures.
3. Conclusion
In conclusion, we report here the synthesis of new and inter-
esting ZNHZCOZCH-bridged or ZN-bridged pyrrole±
pyrazole systems.11,12 It is noteworthy that this protocol
may be useful for the synthesis of compounds possessing
antiviral properties (i.e. distamycin, netropsin, tallimustine
analogues).13 The different reaction behaviour observed is
attributable to the different electronic effects of the substi-
tuents present on the hydrazide derivatives used. When R2 is
an electron-withdrawing group, the C-attack by active
methylene at the terminal carbon of the azoalkene molecule
is favoured. In the absence of this effect, the N-attack takes
place.
4.2.1. Methyl 4-(anilinocarbonyl)-1-[(3-ethoxy-3-oxopro-
panoyl)amino]-2,5-dimethyl-1H-pyrrole-3-carboxylate
5a. Colourless crystals from MeOH; mp 175±1778C; dH
(200 MHz, DMSO-d6) 1.22 (3H, t, Jˆ7.2 Hz, OCH2CH3),
2.13 (3H, s, CH3), 2.30 (3H, s, CH3), 3.54 (2H, s, COCH2,
D2O exch.), 3.65 (3H, s, OCH3), 4.16 (2H, q, Jˆ7.2 Hz,
OCH2CH3), 7.03 (1H, t, Jˆ7.5 Hz, aromatic), 7.29 (2H, t,
Jˆ7.5 Hz, aromatic), 7.66 (2H, d, Jˆ7.5 Hz, aromatic),
10.18 (1H, s, NH), 11.42 (1H, s, NH); dC (50.32 MHz,
DMSO-d6) 9.50 (q), 10.31 (q), 13.93 (q), 40.60 (t), 51.02
(q), 61.03 (t), 107.35 (s), 115.88 (s), 119.28 (d), 122.85 (d),
128.50 (d), 130.50 (s), 134.94 (s), 139.68 (s), 163.35 (s),
164.62 (s), 164.77 (s), 166.97 (s); IR: nmax 3297, 3169,
1751, 1724, 1683, 1635, 1596 cm21; MS: m/z (%) 401
(10) [M1], 309 (100). Anal. Calcd for C20H23N3O6
(401.1): C, 59.84; H, 5.78; N, 10.47. Found: C, 59.66; H,
5.94; N, 10.57.
4. Experimental
4.1. General
Ethyl 3-hydrazino-3-oxopropionate (2a), (4-chlorobenzene-
sulphonyl)acetic acid hydrazide (2b) phenylacetic acid
hydrazide (2d), thiophene-3-acetic acid hydrazide (2e) and
indole-3-acetic acid hydrazide (2f) were commercial
materials and were used without further puri®cation,
whereas 4-nitrophenylacetic acid hydrazide (2c) was
prepared according to a literature procedure. Chlorohydra-
zone derivatives 3a±f were synthesised according to our
published procedures.8,9 1,2-Diaza-1,3-butadienes 6a±g
were synthesised according to published procedures14,15
and used as isomeric mixtures. Sodium methoxide, sodium
hydride and solvents were purchased and used without
further puri®cation with the exception of THF, which was
distilled from sodium hydroxide. Melting points were deter-
mined in open capillary tubes and are uncorrected. IR-FT
spectra were obtained as Nujol mulls. Mass spectra were
4.2.2. Methyl 4-acetyl-1-[(3-ethoxy-3-oxopropanoyl)-
amino]-2,5-dimethyl-1H-pyrrole-3-carboxylate 5b. Colour-
less crystals from EtOAc±Et2O; mp 90±928C; dH
(200 MHz, CDCl3) 1.29 (3H, t, Jˆ7.2 Hz, OCH2CH3),
1.88 (3H, s, CH3), 2.18 (3H, s, CH3), 2.39 (3H, s,
COCH3), 3.52 (2H, s, COCH2, D2O exch.), 3.78 (3H,
s, OCH3), 4.23 (2H, q, Jˆ7.2 Hz, OCH2CH3), 10.13
(1H, s, NH); dC (50.32 MHz, CDCl3) 9.22 (q), 10.11
(q), 13.99 (q), 31.18 (q), 40.58 (t), 51.23 (q), 61.91
(t), 108.60 (s), 121.49 (s), 131.05 (s), 136.02 (s),
164.58 (s), 165.01 (s), 167.05 (s), 202.58 (s); IR: nmax
3207, 1743, 1718, 1704, 1646 cm21; MS: m/z (%) 324
(30) [M1], 292 (100). Anal. Calcd for C15H20N2O6
(324.3): C, 55.55; H, 6.22; N, 8.64. Found: C, 55.40;
H, 6.34; N, 8.56.
1
made at an ionising voltage of 70 eV. All H NMR and
13C NMR spectra were recorded at 200 MHz and at
50.32 MHz respectively. Chemical shifts (dH) are reported
relative to TMS as internal standard. All coupling constant
(J) values are given in hertz. Chemical shifts (dC) are
reported relative to DMSO-d6 or CDCl3 as internal stan-
dards in a broad-band decoupled mode; the multiplicities
were obtained by using 1358 and 908 DEPT experiments
to aid in assignment (qˆmethyl, tˆmethylene, dˆmethyne,
sˆquaternary). The abbreviations used are as follows: s,
singlet; d, doublet; dd, double doublet; t, triplet; q, quartet;
m, multiplet; br, broad; D2O exch., exchanged with D2O; all
the NH and NH2 exchanged with D2O. Precoated silica gel
plates of 0.25 mm were employed for analytical thin layer
chromatography and silica gel 35±70 mm for column
chromatography.
4.2.3. Methyl 4-(anilinocarbonyl)-1-{[2-(4-chlorobenzen-
sulphonyl)acetyl]amino}-2,5-dimethyl-1H-pyrrole-3-car-
boxylate 5c. Colourless crystals from MeOH; mp 204±
2068C; dH (200 MHz, DMSO-d6) 2.07 (3H, s, CH3), 2.25
(3H, s, CH3), 3.37 (3H, s, OCH3), 4.66 (2H, s, COCH2, D2O
exch.), 7.03 (1H, t, Jˆ7.5 Hz, aromatic), 7.29 (2H, t,
Jˆ7.5 Hz, aromatic), 7.67 (2H, d, Jˆ7.5 Hz, aromatic),
7.77 (2H, d, Jˆ8.2 Hz, aromatic), 7.94 (2H, d, Jˆ8.2 Hz,
aromatic), 10.16 (1H, s, NH), 11.69 (1H, br s, NH); dC
(50.32 MHz, DMSO-d6) 9.42 (q), 10.22 (q), 51.05 (q),
59.01 (t), 107.53 (s), 116.04 (s), 119.32 (d), 122.90 (s),
128.51 (d), 129.49 (d), 130.21 (d), 134.68 (s), 137.52 (s),
139.42 (s), 139.62 (s), 160.64 (s), 163.24 (s), 164.50 (s); IR:
nmax 3304, 3172, 1720, 1686, 1636, 1597, 1546, 1339,
4.2. General procedure for the preparation of 1-amino-
pyrrole derivatives 5a±g
a-Chlorohydrazone derivative 3a±f (1.0 mmol) was added
portionwise to a stirred suspension of acetoacetanilide 4a

O. A. Attanasi et al. / Tetrahedron 57 (2001) 1387±1394
1391
1147 cm21; MS: m/z (%) 503 (7) [M1], 411 (100). Anal.
Calcd for C23H22N3O6SCl (503.9): C, 54.82; H, 4.40; N,
8.34. Found: C, 54.72; H, 4.38; N, 8.48.
164.70 (s), 170.34 (s), 196.73 (s); IR: nmax 3342, 3234,
3065, 1695, 1660, 1538 cm21; MS: m/z (%) 367 (98) [M1],
335 (100). Anal. Calcd for C20H21N3O4 (367.4): C, 65.38; H,
5.76; N, 11.44. Found: C, 65.25; H, 5.69; N, 11.40.
4.2.4. Ethyl 4-acetyl-1-{[2-(4-nitrophenyl)acetyl]amino}-
2,5-dimethyl-1H-pyrrole-3-carboxylate 5d. Colourless
crystals from EtOAc±Et2O; mp 161±1658C; dH
(200 MHz, DMSO-d6) 1.24 (3H, t, Jˆ7.1 Hz, OCH2CH3),
2.01 (3H, s, CH3), 2.15 (3H, s, CH3), 2.28 (3H, s, COCH3),
3.91 (2H, s, COCH2, D2O exch.), 4.19 (2H, q, Jˆ7.1 Hz,
OCH2CH3), 7.63 (2H, d, Jˆ8.8 Hz, aromatic), 8.23 (2H, d,
Jˆ8.8 Hz, aromatic), 11.44 (1H, s, NH); dC (50.32 MHz,
DMSO-d6) 9.56 (q), 9.96 (q), 14.03 (q), 30.86 (q), 39.45 (t),
59.77 (t), 108.76 (s), 120.36 (s), 123.52 (d), 130.59 (d),
131.76 (s), 134.42 (s), 142.59 (s), 146.61 (s), 164.16 (s),
168.81 (s), 196.70 (s); IR: nmax 3178, 1702, 1672, 1666,
1517, 1355 cm21; MS: m/z (%) 387 (20) [M1], 341 (82),
178 (100). Anal. Calcd for C19H21N3O6 (387.4): C, 58.91; H,
5.46; N, 10.85. Found: C, 57.85; H, 5.32; N, 10.46.
4.3. General procedure for the preparation of hydrazone
1,4-adducts 7a±i
1,2-Diaza-1,3-butadiene 6a±g (1.0 mmol) dissolved in THF
(5 ml) was slowly added to a magnetically stirred solution of
the pyrrole derivative 5a,b,d±g (1.0 mmol) in THF (5 ml)
containing a catalytic amount of sodium methoxide. The
reaction mixture was allowed to stand at room temperature
until the complete disappearance of the reagents (24±120 h,
monitored by TLC). The solvent was removed under
reduced pressure and the residue, dissolved in ethyl acetate,
was washed with water in a separatory funnel. The organic
layer, dried over anhydrous Na2SO4, was evaporated in
vacuo. Derivatives 7a±i were obtained as diastereomeric
mixtures after a chromatographic puri®cation on a silica
gel column (cyclohexane±ethyl acetate mixtures as eluent)
followed by crystallisation from appropriate solvents.
4.2.5. Ethyl 4-acetyl-1-[(2-phenylacetyl)amino]-2,5-di-
methyl-1H-pyrrole-3-carboxylate 5e. White powder
from Et2O; mp 100±1028C; dH (200 MHz, DMSO-d6)
1.23 (3H, t, Jˆ7.1 Hz, OCH2CH3), 1.96 (3H, s, CH3), 2.12
(3H, s, CH3), 2.27 (3H, s, COCH3), 3.69 (2H, s, COCH2),
4.19 (2H, q, Jˆ7.1 Hz, OCH2CH3), 7.30±7.37 (5H, m,
aromatic), 11.35 (1H, s, NH); dC (50.32 MHz, DMSO-d6)
9.54 (q), 9.95 (q), 14.07 (q), 30.88 (q), 39.94 (t), 59.78 (t),
108.72 (s), 120.33 (s), 126.92 (d), 128.49 (d), 129.05 (d),
131.86 (s), 134.50 (s), 134.78 (s), 164.21 (s), 169.78 (s),
196.74 (s); IR: nmax 3182, 1703, 1678, 1657 cm21; MS:
m/z (%) 342 (44) [M1], 296 (100). Anal. Calcd for
C19H22N2O4 (342.4): C, 66.65; H, 6.48; N, 8.18. Found: C,
66.72; H, 6.32; N, 7.98.
7a. White powder from Et2O±petroleum ether (40±608C);
dH (200 MHz, DMSO-d6) 1.15±1.26 (6H, m, 2£OCH2CH3),
1.43±1.47 (9H, m, OBut), 1.94±2.27 (9H, m, 3£CH3), 3.64
(3H, s, OCH3), 3.89±4.01 (1H, m, CH), 4.08±4.19 (4H, m,
2£OCH2CH3), 4.21±4.37 (1H, m, CH, D2O exch.), 7.03
(1H, t, Jˆ7.3 Hz, aromatic), 7.30 (2H, t, Jˆ7.3 Hz,
aromatic), 7.68 (2H, d, Jˆ7.3 Hz, aromatic), 9.79 (1H, br
s, NH), 10.16 (1H, br s, NH), 11.88 (1H, br s, NH); dC
(50.32 MHz, DMSO-d6) 9.05 and 9.30 (2q), 9.86 and
10.06 (2q) 13.75 (q), 13.86 (q), 16.43 and 16.83 (2q),
28.02 (q), 50.40 (d), 51.03 (q), 52.34 (d), 61.17 and 61.28
(2t), 61.48 and 61.69 (2t), 79.30 and 79.41 (2s), 107.23 and
107.38 (2s), 115.76 and 115.94 (2s), 119.29 (d), 122.86 (d),
128.49 (d), 130.17 and 130.72 (2s), 134.86 and 135.26 (2s),
139.66 (s), 146.05 and 146.64 (2s), 152.73 (s), 163.27 (s),
165.19 and 164.54 (2s), 166.10 and 166.99 (2s), 167.57 (s),
169.42 (s); IR: nmax 3289, 3194, 3133, 1747, 1707, 1658,
1640, 1599 cm21. Anal. Calcd for C31H41N5O10 (324.4): C,
57.84; H, 6.42; N, 10.88. Found: C, 57.70; H, 6.50; N, 10.72.
4.2.6. Ethyl 4-acetyl-1-{[2-(3-thienyl)acetyl]amino}-2,5-
dimethyl-1H-pyrrole-3-carboxylate 5f. Colourless crys-
tals from EtOAc±cyclohexane; mp 114±1158C; dH
(200 MHz, DMSO-d6) 1.24 (3H, t, Jˆ7.0 Hz, OCH2CH3),
2.00 (3H, s, CH3), 2.14 (3H, s, CH3), 2.28 (3H, s, COCH3),
3.72 (2H, s, COCH2), 4.19 (2H, q, Jˆ7.0 Hz, OCH2CH3),
7.09 (1H, d, Jˆ4.9 Hz, aromatic), 7.38 (1H, d, Jˆ1.9 Hz,
aromatic), 7.52 (1H, dd, Jˆ4.9, 1.9 Hz, aromatic) 11.32
(1H, s, NH); dC (50.32 MHz, DMSO-d6) 9.52 (q), 9.92
(q), 14.03 (q), 30.85 (q), 34.73 (t), 59.75 (t), 108.88 (s),
120.30 (s), 123.07 (d), 128.29 (d), 128.38 (d), 131.82 (s),
134.23 (s), 134.49 (s), 164.18 (s), 169.35 (s), 196.71 (s); IR:
nmax 3204, 3117, 3093, 1711, 1696, 1655 cm21; MS: m/z
(%) 348 (79) [M1], 302 (100). Anal. Calcd for C17H20N2O4S
(348.4): C, 58.60; H, 5.79; N, 8.04. Found: C, 58.44; H,
5.65; N, 8.11.
7b. White powder from MeOH; dH (200 MHz, DMSO-d6)
1.14±1.25 (3H, m, OCH2CH3), 1.83±2.24 (9H, m, 3£CH3),
3.64 (3H, s, OCH3), 3.67 (3H, s, OCH3), 3.93±4.01 (1H, m,
CH), 4.15±4.21 (2H, m, OCH2CH3), 4.29±4.36 (1H, m, CH,
D2O exch.), 5.14±5.19 (2H, m, OCH2Ph), 6.99±7.08 (1H,
m, aromatic), 7.25±7.36 (7H, m, aromatic), 7.65±7.72 (2H,
m, aromatic), 10.14 and 10.15 (1H, 2 s, NH), 10.26 (1H, br
s, NH), 11.33 (1H, s, NH); dC (50.32 MHz, DMSO-d6) 9.03
and 9.35 (2q), 9.84 and 10.04 (2q), 13.85 and 14.06 (2q),
16.48 and 16.57 (2q), 50.47 (d), 51.02 (q), 52.15 (d), 61.59
and 61.79 (2t), 65.86 (t), 107.36 and 107.41 (2s), 115.99 (s),
119.28 (d), 122.89 (d), 127.92 (d), 128.32 (d), 128.38 (d),
128.53 (d), 130.17 and 130.26 (2s), 147.01 and 147.52 (2s),
153.71 (s), 163.29 (s), 164.29 and 165.11 (2s), 166.04 and
166.93 (2s), 167.51 (s), 169.99 (s); IR: nmax 3172, 3033,
1747, 1721, 1707, 1680, 1650, 1599 cm21. Anal. Calcd
for C33H37N5O10 (663.7): C, 59.72; H, 5.62; N, 10.55.
Found: C, 59.58; H, 5.68; N, 10.46.
4.2.7. Methyl 4-acetyl-1-{[2-(1H-indol-3-yl)acetyl]amino}-
2,5-dimethyl-1H-pyrrole-3-carboxylate 5g. White powder
from EtOAc; mp 165±1668C; dH (200 MHz, DMSO-d6) 1.99
(3H, s, CH3), 2.12 (3H, s, CH3), 2.27 (3H, s, COCH3), 3.71
(3H, s, OCH3), 3.80 (2H, s, COCH2), 7.00±7.13 (2H, m,
aromatic), 7.31 (1H, s, aromatic), 7.39 (1H, d, Jˆ7.5 Hz,
aromatic), 7.61 (1H, d, Jˆ7.5 Hz, aromatic), 11.00 (1H, s,
NH), 11.26 (1H, s, NH); dC (50.32 MHz, DMSO-d6) 9.59 (q),
9.94 (q), 30.41 (t), 30.70 (q), 51.13 (q), 108.04 (s), 108.45 (s),
111.49 (d), 118.34 (d), 118.53 (d), 120.26 (s), 121.18 (d),
124.26 (d), 126.92 (s), 132.15 (s), 134.69 (s), 135.98 (s),
7c. Colourless crystals from EtOAc; dH (200 MHz, CDCl3)

1392
O. A. Attanasi et al. / Tetrahedron 57 (2001) 1387±1394
1.22±1.31 (6H, m, 2£OCH2CH3), 1.91±2.41 (12H, m,
3£CH3 and COCH3), 3.73 (3H, s, OCH3), 3.79 (3H, s,
OCH3), 4.06±4.26 (5H, m, 2£OCH2CH3 and CH), 4.55±
4.60 (1H, m, CH, D2O exch.), 8.06 and 8.18 (1H, 2 br s,
NH), 10.05 (1H, br s, NH); IR: nmax 3293, 3229, 3178, 1759,
1745, 1732, 1712, 1685, 1645 cm21. Anal. Calcd for
C23H32N4O10 (524.5): C, 52.67; H, 6.15; N, 10.68. Found:
C, 52.58; H, 6.18; N, 10.56.
(1H, s, NH); IR: nmax 3286, 3101, 1751, 1687, 1537 cm21
.
Anal. Calcd for C24H30N4O8S (534.6): C, 53.92; H, 5.66; N,
10.48. Found: C, 53.74; H, 5.62; N, 10.56.
7i. White powder from EtOAc±Et2O; dH (200 MHz,
DMSO-d6) 1.08±1.16 (3H, m, OCH2CH3), 1.78 (3H, s,
CH3), 1.99, 2.05, 2.16, 2.23, 2.28 and 2.30 (9H, 6 s,
2£CH3 and COCH3), 3.34 (2H, br s, COCH2), 3.64 (3H, s,
OCH3), 3.75 (3H, s, OCH3), 4.05±4.16 (2H, m, OCH2CH3),
5.04 and 5.09 (1H, 2 s, CH), 6.95±7.10 (3H, m, aromatic),
7.27±7.36 (2H, m, aromatic), 10.17 (1H, s, NH), 10.98 (1H,
s, NH); IR: nmax 3294, 3178, 1752, 1735, 1710, 1683,
1575 cm21. Anal. Calcd for C28H33N5O8 (567.6): C, 59.25;
H, 5.86; N, 12.34. Found: C, 59.17; H, 6.02; N, 12.45.
7d. White powder from Et2O; dH (200 MHz, DMSO-d6)
1.18±1.29 (6H, m, 2£OCH2CH3), 1.44 (9H, s, OBut),
1.48, 1.62 and 1.72 (6H, 3 s, 2£CH3), 2.12, 2.23, 2.26 and
2.28 (6H, 4 s, CH3 and COCH3), 4.12±4.25 (5H, m, CH and
2£OCH2CH3), 4.69 (1H, d, Jˆ11.7 Hz, CH, D2O exch.),
7.72 (2H, d, Jˆ8.5 Hz, aromatic), 8.20 (2H, d, Jˆ8.5 Hz,
aromatic), 9.54 (1H, s, NH), 11.76 (1H, s, NH); IR: nmax
3284, 3193, 1743, 1715, 1681, 1651, 1605, 1521,
1348 cm21. Anal. Calcd for C30H39N5O10 (629.6): C,
57.23; H, 6.24; N, 11.12. Found: C, 57.28; H, 6.18; N, 11.26.
4.4. General procedure for the preparation of pyrrolo-
pyrazole derivatives 8a±i
To a magnetically stirred solution of 1,4-adduct 7a±i
(1.0 mmol) in a 1:1 mixture of THF±MeOH (10 ml) was
added sodium hydride 60% pure in mineral oil (1.1 mmol).
The reaction mixture was allowed to stand at room tempera-
ture until the complete disappearance of hydrazone
compounds 7a±i (6±48 h, monitored by TLC). THF was
removed under reduced pressure and the residue was
suspended in ethyl acetate, acidi®ed in a separatory funnel
with 2N HCl until pH 1 and then washed with water. The
organic layer, dried over anhydrous Na2SO4, was evapo-
rated in vacuo. The crude reaction mixture was crystallised
from appropriate solvents as in the case of 8a±c or puri®ed
by chromatography and subsequent crystallisation as for
compounds 8d±i. Compounds 8a±i were obtained as
mixtures of conformers, as revealed by DNMR experiments
in DMSO-d6 (293±360 K).
7e. White powder from EtOAc±Et2O; dH (200 MHz,
DMSO-d6) 1.15±1.27 (3H, m, OCH2CH3), 1.47, 1.61 and
1.66 (6H, 3 s, 2£CH3), 2.12, 2.22, 2.25 and 2.27 (6H, 4 s,
CH3 and COCH3), 3.68 (3H, s, OCH3), 4.12±4.32 (3H, m,
CH and OCH2CH3), 4.86 (1H, d, Jˆ11.7 Hz, CH, D2O
exch.), 6.22 (2H, br s, NH2), 7.72 (2H, d, Jˆ8.5 Hz,
aromatic), 8.20 (2H, d, Jˆ8.5 Hz, aromatic), 9.10 (1H, s,
NH), 11.80 (1H, s, NH); IR: nmax 3407, 3388, 3178, 1736,
1702, 1666, 1646, 1569, 1351 cm21. Anal. Calcd for
C25H30N6O9 (558.5): C, 53.77; H, 5.41; N, 15.05. Found:
C, 53.65; H, 5.52; N, 15.23.
7f. White powder from THF; dH (200 MHz, DMSO-d6)
1.16±1.25 (3H, m, OCH2CH3), 1.63 and 1.65 (3H, 2 s,
CH3), 2.02, 2.16, 2.20, 2.29, 2.31 and 2.33 (9H, 6 s,
2£CH3 and COCH3), 3.32 (2H, br s, COCH2), 3.74 (3H, s,
OCH3), 4.12±4.22 (2H, m, OCH2CH3), 5.50 and 5.54 (1H, 2
s, CH), 6.96±7.06 (3H, m, aromatic), 7.24±7.31 (5H, m,
aromatic), 7.53 (2H, d, Jˆ7.9 Hz, aromatic), 8.87 and
8.89 (1H, 2 s, NH), 9.96 (1H, s, NH); IR: nmax 3324,
3195, 3132, 3092, 3061, 3029, 2963, 1759, 1743, 1716,
8a. White powder from Et2O±MeOH; dH (200 MHz,
DMSO-d6) 1.21 (3H, t, Jˆ7.2 Hz, OCH2CH3), 1.53 (9H, s,
OBut), 2.02, 2.14, 2.19 and 2.33 (9H, 4 s, 3£CH3), 3.63 and
3.65 (3H, 2 s, OCH3), 4.19 (2H, q, Jˆ7.2 Hz, OCH2CH3),
4.64 (1H, s, CH, D2O exch.), 7.03 (1H, t, Jˆ7.7 Hz,
aromatic), 7.29 (2H, t, Jˆ7.7 Hz, aromatic), 7.67 (2H, d,
Jˆ7.7 Hz, aromatic), 10.16 (1H, s, NH), 11.58 (1H, br s,
NH), 11.72 (1H, br s, NH); dC (50.32 MHz, DMSO-d6) 9.46
(q), 10.26 (q), 11.90 (q), 13.93 (q), 27.64 (q), 45.08 (d),
51.05 (q), 61.65 (t), 84.03 (s), 96.53 (s), 107.39 (s),
115.82 (s), 119.27 (d), 119.37 (s), 122.93 (d), 128.53 (d),
130.72 (s), 135.14 (s), 139.59 (s), 146.42 (s), 151.89 (s),
163.25 (s), 164.63 (s), 166.54 (s), 167.87 (s); IR: nmax
3170, 3120, 1755, 1730, 1695, 1665, 1635, 1610,
1590 cm21. Anal. Calcd for C29H35N5O9 (597.6): C, 58.28;
H, 5.90; N, 11.72. Found: C, 58.36; H, 5.78; N, 11.64.
1707, 1678, 1622, 1596 cm21
.
Anal. Calcd for
C31H35N5O7 (589.6): C, 63.15; H, 5.98; N, 11.88. Found:
C, 63.00; H, 5.98; N, 11.75.
7g. Yellowish foam; dH (200 MHz, DMSO-d6) 1.14±1.29
(6H, m, 2£OCH2CH3), 1.60 (3H, s, CH3), 1.98, 2.09, 2.17,
2.28, 2.31 and 2.32 (9H, 6 s, 2£CH3 and COCH3), 3.29 (2H,
br s, COCH2), 4.12±4.26 (4H, m, 2£OCH2CH3), 5.21 and
5.24 (1H, 2 s, CH), 6.42 (2H, br s, NH2), 7.01±7.05 (2H, m,
aromatic), 7.22±7.29 (3H, m, aromatic), 9.43 (1H, s, NH);
IR: nmax 3480, 3361, 3304, 3220, 1748, 1716, 1701, 1686,
1656, 1638, 1576 cm21. Anal. Calcd for C26H33N5O7
(527.5): C, 59.19; H, 6.30; N, 13.27. Found: C, 59.30; H,
6.18; N, 13.32.
8b. Whitish powder from EtOAc±Et2O; dH (200 MHz,
DMSO-d6) 1.20 (3H, t, Jˆ7.0 Hz, OCH2CH3), 2.01, 2.15,
2.19 and 2.33 (9H, 4 s, 3£CH3), 3.63 and 3.64 (3H, 2 s,
OCH3), 4.19 (2H, q, Jˆ7.0 Hz, OCH2CH3), 4.66 (1H, s, CH,
D2O exch.), 5.40 (2H, s, OCH2Ph), 7.02 (1H, t, Jˆ7.2 Hz,
aromatic), 7.25±7.51 (7H, m, aromatic), 7.67 (2H, d,
Jˆ7.2 Hz, aromatic), 10.18 (1H, s, NH), 11.60 (1H, s,
NH), 12.01 (1H, br s, NH); dC (50.32 MHz, DMSO-d6)
9.49 (q), 10.30 (q), 12.00 (q), 13.94 (q), 45.07 (d), 51.05
(q), 61.67 (t), 68.08 (t), 96.47 (s), 107.42 (s), 115.90 (s),
119.34 (d), 119.38 (s), 122.89 (d), 127.92 (d), 128.29 (d),
7h. White foam; dH (200 MHz, DMSO-d6) 1.25 (3H, t,
Jˆ7.0 Hz, OCH2CH3), 1.77 (3H, s, CH3), 2.03, 2.08, 2.21,
2.27, 2.30 and 2.31 (9H, 6 s, 2£CH3 and COCH3), 3.29 (2H,
br s, COCH2), 3.65 (3H, s, OCH3), 3.70 (3H, s, OCH3), 4.21
(2H, q, Jˆ7.0 Hz, OCH2CH3), 5.15 and 5.19 (1H, 2 s, CH),
6.86 (1H, d, Jˆ4.9 Hz, aromatic), 7.13 (1H, d, Jˆ1.9 Hz,
aromatic), 7.45 (1H, dd, Jˆ4.9, 1.9 Hz, aromatic) 10.21

O. A. Attanasi et al. / Tetrahedron 57 (2001) 1387±1394
1393
128.47 (d), 128.53 (d), 130.40 (s), 134.79 (s), 135.11 (s),
139.70 (s), 147.90 (s), 153.01 (s), 163.35 (s), 164.65 (s),
166.53 (s), 167.83 (s); IR: nmax 3288, 3187, 1770, 1736,
8h. Light pink powder from Et2O; dH (200 MHz, DMSO-d6)
1.23 (3H, t, Jˆ7.0 Hz, OCH2CH3), 1.62 (3H, s, CH3), 2.03,
2.11, 2.15, 2.25 and 2.29 (9H, 5 s, 2£CH3 and COCH3),
3.65±3.78 (4H, m, OCH3 and COCHaHb), 3.99 (1H, d,
Jˆ16.0 Hz, COCHaHb), 4.16 (2H, q, Jˆ7.0 Hz,
OCH2CH3), 6.88 (1H, d, Jˆ4.9 Hz, aromatic), 7.15 (1H,
d, Jˆ1.9 Hz, aromatic), 7.44 (1H, dd, Jˆ4.9, 1.9 Hz,
aromatic), 11.52 (1H, br s, NH); IR: nmax 3353, 3105,
1748, 1734, 1698, 1669, 1559, 1540 cm21. Anal. Calcd
for C23H26N4O7S (502.5): C, 54.97; H, 5.21; N, 11.15.
Found: C, 54.96; H, 5.11; N, 11.20.
1694, 1642, 1600, 1577 cm21
.
Anal. Calcd for
C32H33N5O9 (631.6): C, 60.85; H, 5.27; N, 11.09. Found:
C, 60.74; H, 5.14; N, 11.09.
8c. Colourless crystals from MeOH; dH (200 MHz, DMSO-
d6) 1.20 (3H, t, Jˆ7.0 Hz, OCH2CH3), 1.98, 2.11, 2.14, 2.24
and 2.28 (12H, 5 s, 3£CH3 and COCH3), 3.73 (3H, s,
OCH3), 3.89 (3H, s, OCH3), 4.19 (2H, q, Jˆ7.0 Hz,
OCH2CH3), 4.66 (1H, s, CH, D2O exch.), 11.61 (1H, s,
NH), 12.02 (1H, br s, NH); dC (200 MHz, DMSO-d6) 9.50
(q), 9.86 (q), 11.89 (q), 13.89 (q), 30.70 (q), 44.95 (d), 51.15
(q), 53.90 (q), 61.64 (t), 96.20 (s), 108.60 (s), 120.37 (s),
120.63 (s), 132.04 (s), 134.63 (s), 148.44 (s), 152.61 (s),
164.61 (s), 166.55 (s), 167.79 (s) 196.55 (s); IR: nmax
8i. Beige powder from Et2O; dH (200 MHz, DMSO-d6) 1.54
and 1.56 (3H, 2 s, CH3), 1.88 and 1.96 (3H, 2 s, CH3), 2.16,
2.22, 2.25 and 2.28 (6H, 4 s, CH3 and COCH3), 3.68 (3H, s,
OCH3), 3.77±3.83 (4H, m, OCH3 and COCHaHb), 4.06 (1H,
d, Jˆ14.0 Hz, COCHaHb), 6.89±7.09 (3H, m, aromatic),
7.31±7.46 (2H, m, aromatic), 10.92 (1H, s, NH), 11.52
(1H, br s, NH); IR: nmax 3349, 3301, 1736, 1685,
1616 cm21. Anal. Calcd for C26H27N5O7 (521.5): C, 59.88;
H, 5.22; N, 13.43. Found: C, 59.88; H, 5.18; N, 13.48.
3172, 3127, 1780, 1741, 1702, 1650, 1577, 1541 cm21
.
Anal. Calcd for C21H26N4O9 (478.5): C, 52.72; H, 5.48; N,
11.71. Found: C, 52.64; H, 5.46; N, 11.65.
8d. Yellow powder from Et2O; dH (200 MHz, DMSO-d6)
1.24 (3H, t, Jˆ7.0 Hz, OCH2CH3), 1.51 (9H, s, OBut), 1.97,
(3H, s, CH3), 2.05, (3H, s, CH3), 2.18, (3H, s, CH3), 2.27
(3H, s, COCH3), 4.19 (2H, q, Jˆ7.0 Hz, OCH2CH3), 5.07
and 5.15 (1H, 2 s, CH, D2O exch.), 7.87 (2H, d, Jˆ8.7 Hz,
aromatic), 8.20 (2H, d, Jˆ8.7 Hz, aromatic), 11.67 (2H, br
s, 2 NH); IR: nmax 3197, 1760, 1701, 1683, 1652, 1606,
1595, 1521, 1348 cm21. Anal. Calcd for C28H33N5O9
(583.6): C, 57.63; H, 5.70; N, 12.00. Found: C, 57.50; H,
5.78; N, 11.82.
4.4.1. Methyl 4-(anilinocarbonyl)-2,5-dimethyl-1H-pyr-
role-3-carboxylate 9. White powder from EtOAc±cyclo-
hexane; mp 206±2108C; dH (200 MHz, DMSO-d6) 2.31
(3H, s, CH3), 2.38 (3H, s, CH3), 3.70 (3H, s, OCH3), 7.01
(1H, t, Jˆ7.5 Hz, aromatic), 7.29 (2H, t, Jˆ7.5 Hz,
aromatic), 7.66 (2H, d, Jˆ7.5 Hz, aromatic), 10.76 (1H, s,
NH), 11.51 (1H, br s, NH); dC (200 MHz, DMSO-d6) 12.47
(q), 13.55 (q), 51.10 (q), 108.03(s), 116.24 (s), 119.10 (d),
122.62 (d), 128.58 (d), 131.63 (s), 134.79 (s), 139.79 (s),
163.36 (s), 166.42 (s); IR: nmax 3209, 3126, 1674, 1653,
1598 cm21. MS: m/z (%) 272 (14) [M1], 180 (100), 150
(28). Anal. Calcd for C15H16N2O3 (272.3): C, 66.16; H,
5.92; N, 10.29. Found: C, 66.28; H, 5.90; N, 10.23.
8e. Light yellow powder from Et2O; dH (200 MHz, DMSO-
d6) 1.19±1.26 (3H, m, OCH2CH3), 1.55 and 1.69 (3H, 2 s,
CH3), 2.06±2.28 (9H, m, 2£CH3 and COCH3), 4.04±4.21
(2H, m, OCH2CH3), 5.84 and 5.92 (1H, 2 s, CH, D2O exch.),
6.11 and 6.86 (2H, 2 br s, NH2) 7.05, 7.82, 8.00 and 8.17
(4H, 4 d, Jˆ8.5 Hz, aromatic), 9.03 (1H, s, NH), 11.48 (1H,
br s, NH); IR: nmax 3355, 3219, 1734, 1699, 1688, 1653,
1637, 1572, 1522, 1349 cm21. Anal. Calcd for C24H26N6O8
(526.5): C, 54.75; H, 4.98; N, 15.96. Found: C, 54.90; H,
4.96; N, 15.87.
Acknowledgements
This investigation was supported by ®nancial assistance
Á
from the Universita degli Studi di Urbino and Consiglio
Nazionale delle Ricerche (CNR-Roma). The authors thank
Dr Barbara Guidi for her generous help in the DNMR
experiments.
8f. White powder from Et2O; dH (200 MHz, DMSO-d6)
1.20±1.26 (3H, m, OCH2CH3), 1.70 and 1.81 (3H, 2 s,
CH3), 1.93, 2.04, 2.16 and 2.26, (9H, 4 s, 2£CH3 and
COCH3), 3.68±3.96 (2H, m, COCH2), 4.16±4.21 (2H, m,
OCH2CH3), 7.08±7.27 (8H, m, aromatic), 7.56±7.62 (2H,
m, aromatic), 10.01 and 10.10 (1H, 2 br s, NH), 12.32 (1H,
br s, NH); IR: nmax 3264, 3169, 2986, 1735, 1702, 1686,
1662, 1619, 1604 cm21. Anal. Calcd for C30H31N5O6
(557.6): C, 64.62; H, 5.60; N, 12.56. Found: C, 64.58; H,
5.68; N, 12.56.
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Á
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8g. Whitish powder from Et2O; dH (200 MHz, DMSO-d6)
1.19±1.27 (3H, m, OCH2CH3), 1.73 and 1.86 (3H, 2 s, CH3),
1.98, 2.03, 2.18, 2.26 and 2.32 (9H, 5 s, 2£CH3 and
COCH3), 3.63±3.96 (2H, m, COCH2), 4.15±4.22 (2H, m,
OCH2CH3), 7.16±7.33 (5H, m, aromatic), 8.07 and 8.19
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3218, 1750, 1732, 1718, 1699, 1685, 1669, 1655,
1576 cm21. Anal. Calcd for C24H27N5O6 (481.5): C, 59.87;
H, 5.65; N, 14.54. Found: C, 59.78; H, 5.62; N, 14.49.
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