Reaction of ethyl 4-[(E)-1-chloro-3-oxoprop-1-en-1-yl]-3,5-dimethyl-1H- pyrrole-2-carboxylate with hydrazines

Article abstract of DOI:10.1134/S1070428009040162

Ethyl 4-[(E)-1-chloro-3-oxoprop-1-en-1-yl]-3,5-dimethyl-1H-pyrrole-2- carboxylate reacted with substituted hydrazines in different solvents to give mixtures of regioisomeric 3- and 5-substituted pyrazoles. Conditions were found for selective formation of

Full text of DOI:10.1134/S1070428009040162

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 4, pp. 564–571. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © E.I. Mikhed’kina, O.S. Bylina, I.I. Mel’nik, D. T. Kozhich, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 4,
pp. 578–585.
Reaction of Ethyl 4-[(E)-1-Chloro-3-oxoprop-1-en-1-yl]-
3,5-dimethyl-1H-pyrrole-2-carboxylate with Hydrazines
E. I. Mikhed’kinaa, O. S. Bylinaa, I. I. Mel’nika, and D. T. Kozhichb
a “Kharkov Polytechnical Institute” National Technical University, ul. Frunze 21, Kharkov, 61002 Ukraine
e-mail: bylina@sphere.kharkov.com
b Medical Biology Institute, Minsk, Belarus
Received July 1, 2008
Abstract—Ethyl 4-[(E)-1-chloro-3-oxoprop-1-en-1-yl]-3,5-dimethyl-1H-pyrrole-2-carboxylate reacted with
substituted hydrazines in different solvents to give mixtures of regioisomeric 3- and 5-substituted pyrazoles.
Conditions were found for selective formation of 1-aryl(alkyl)-5-(5-ethoxycarbonyl-2,4-dimethyl-1H-pyrrol-
3-yl)-1H-pyrazoles.
DOI: 10.1134/S1070428009040162
Reactions of β-chloro-substituted α,β-unsaturated
aldehydes with difunctional nucleophiles are widely
used in the synthesis of various heterocyclic com-
pounds, including pyrazole derivatives [1–3]. Pyrazole
ring is a structural fragment of some pharmaceutical
agents [4–6]. 1,5- and 1,3-Diarylpyrazoles exhibit anti-
septic, analgesic, antiphlogistic [7], anticarcinogenic
[8], and herbicidal activity [9, 10]. Molecules of many
natural compounds contain a pyrrole ring [11, 12].
Numerous compounds of pharmacological interest
have been created on the basis of pyrrole derivatives
[13, 14]. It may be anticipated that combination of
pyrazole and pyrrole rings in a single molecule would
give rise to new interesting properties.
intermediate product in the synthesis of various or-
ganic compounds having a pyrazole ring.
It is known that reactions of β-chloro-α,β-unsatu-
rated aldehydes with arylhydrazines are often non-
selective, and mixtures of isomeric 1,3- and 1,5-di-
substituted pyrazoles at different ratios are formed
[16, 17]. The resulting isomer mixtures are often dif-
ficult to separate; therefore, development of regio-
selective procedures for the synthesis of required pyra-
zole derivatives is an important problem.
We found that compound I reacts with phenyl-
hydrazine (IIa) in ethanol to give a mixture of two
products, presumably 5- and 3-substituted pyrazoles
IIIa and IVa, with an overall yield of 67% (Scheme 1).
1
In the present article were report the results of our
study on the reaction of ethyl 4-[(E)-1-chloro-3-oxo-
prop-1-en-1-yl]-3,5-dimethyl-1H-pyrrole-2-carbox-
ylate (I) with hydrazines. Accessible ester I possessing
a chlorovinylcarbaldehyde fragment was prepared
from ethyl 4-acetyl-3,5-dimethyl-1H-pyrrole-2-carbox-
ylate according to Vilsmeier–Haak [15]. It is a reactive
In the H NMR spectrum of the product mixture we
observed signals from protons in the pyrazole ring as
doublets at δ 6.41 and 7.75 ppm (J = 1.8 Hz) and
δ 6.60 and 8.52 ppm (J = 2.6 Hz). According to the
signal intensities, the isomer ratio was 82:18. We
failed to isolate individual isomers by recrystallization
or chromatography. Using vacuum sublimation we
Scheme 1.
R
N
N
Cl
Me
Me
N
Me
N
RNHNH2 (IIa–IId)
R
CHO
+
O
O
O
Me
N
Me
Me
N
H
N
H
H
EtO
EtO
EtO
I
IIIa–IIId
IVa–IVd
R = Ph (a), 4-MeC6H4 (b), 4-BrC6H4 (c), Me (d).
564

REACTION OF ETHYL 4-[(E)-1-CHLORO-3-OXOPROP-1-EN-1-YL]-...
565
Scheme 2.
OCH
Ph
N
O
Me
NHPh
Me
Me
Me
N
Me
N
PhNHNH2
POCl3, DMF
O
O
O
Me
Me
Me
N
H
N
N
H
H
EtO
EtO
EtO
V
VI
VII
O
Ph
Ph
N
N
HO
Me
[O]
N
Me
O
N
–CO2
O
Me
Me
N
N
H
H
EtO
EtO
VIII
IVa
succeeded in isolating only the minor isomer. When
the reaction of aldehyde I with phenylhydrazine (IIa)
was carried out in anhydrous ethanol, we obtained
80% of a mixture of isomeric pyrazoles at a ratio of
4-H signal of compound IVa also changed its position
insignificantly (Δδ = 0.08 ppm), whereas the down-
field shift of its 5-H signal was Δδ = 0.54 ppm. A prob-
able reason is that the 5-H proton in IVa appears in the
vicinity of the phenyl ring on N1, and change of the
solvent may be accompanied by appreciable variation
of shielding effect of the phenyl ring (due to its mag-
netically anisotropic properties) on the neighboring
proton. This is consistent with the data of [18],
according to which chemical shifts of pyrazole ring
protons depend on the solvent polarity. The above data
provide an indirect support to the assumed structures
of isomeric pyrazoles IIIa and IVa.
1
97:3 (according to the H NMR data). By recrystal-
lization from toluene we isolated the major isomer as
1
individual substance. Its melting point and H NMR
spectrum (position of signals from pyrazole ring pro-
tons and the corresponding coupling constant) differed
from those found for the isomer isolated by vacuum
sublimation. The mass spectra of both isomers contain-
ed the molecular ion peak with m/z 309 (100%, [M]+·).
The structure of pyrazole IVa was confirmed by inde-
pendent synthesis from acetylpyrrole V through hydra-
zone VI and subsequent treatment of VI with phos-
phoryl chloride in dimethylformamide. 4-Formylpyra-
zole VII thus obtained was oxidized with potassium
permanganate to carboxylic acid VIII which under-
went decarboxylation to pyrazole IVa on heating in
quinoline in the presence of copper (Scheme 2). The
resulting pyrazole IVa showed no depression of the
melting point on mixing with the product isolated by
vacuum sublimation, and their spectral parameters
were identical. The structure of pyrazole IVa was un-
ambiguously determined by X-ray analysis (the results
will be reported elsewhere as a part of other study).
The reaction of aldehyde I with phenylhydrazine
(IIa) was carried out in different solvents with a view
to reveal solvent effect on the yield and ratio of iso-
meric pyrazoles. The results are collected in Table 1. It
is seen that the highest yields were obtained in polar
solvents (methanol, ethanol, acetonitrile) and that the
major product was 1,5-disubstituted pyrazole IIIa. We
Table 1. Reaction of aldehyde I with phenylhydrazine (IIa)
in different solvents
Isomer fractions
Overall
yield, %
Solvent
Ethanol
IIIa
IVa
1
Compounds VI–VIII were identified by IR, H NMR,
80
87
68
81
46
40
50
97
95
92
85
81
82
80
03
05
08
15
09
18
20
and mass spectra.
Methanol
1
Comparison of the H NMR spectra of IIIa and
Acetic acid
Acetonitrile
Ethyl acetate
Toluene
IVa, recorded from solutions in CDCl3 and DMSO-d6,
showed that the position of signals from protons in the
pyrazole ring of IIIa changed insignificantly. In going
from CDCl3 to DMSO-d6, the downfield shift Δδ was
0.17 and 0.06 ppm for 3-H and 4-H, respectively. The
Methylene chloride
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 4 2009

MIKHED’KINA et al.
566
3
1
Table 2. Chemical shifts δ and coupling constants J of protons in the pyrazole ring in the H NMR spectra (DMSO-d6) of
isomeric pyrazoles IIIa–IIId and IVa–IVd and their ratios in the reaction mixtures
δ, ppm
δ, ppm
Ratio III:IV, %
Comp.
no.
Comp.
no.
3J, Hz
3J, Hz
3-H
4-H
5-H
4-H
ethanol
acetonitrile
IIIa
IIIb
IIIc
IIId
7.75
7.72
7.77
7.46
6.41
6.38
6.43
6.13
1.8
1.8
1.8
1.8
IVa
IVb
IVc
IVd
8.52
8.46
8.56
7.68
6.60
6.57
6.63
6.23
2.6
2.6
2.6
2.4
91:90
89:11
98:20
79:21
94:60
96:40
100:000
77:23
also examined reactions of aldehyde I with a series of
arylhydrazines having different substituents in the
benzene ring. The reaction with 4-methylphenylhydra-
zine in ethanol was accompanied by fast heterocycliza-
tion, so that we failed to detect intermediate hydrazone
and isolated pyrazole IIIb in 53% yield. Likewise,
from methylhydrazine we obtained pyrazole IIId
(Scheme 1). 4-Nitrophenylhydrazine having an elec-
tron-withdrawing nitro group (which reduces the nu-
cleophilicity of the amino nitrogen atom) reacted with
aldehyde I under analogous conditions to give hydra-
zone IXa, while hydrazone IXb was formed in the
reaction of I with 2,4-dinitrophenylhydrazine only in
the presence of excess sulfuric acid (Scheme 3). Hy-
drazones IXa and IXb did not undergo heterocycliza-
tion on prolonged heating in high-boiling solvents
even in the presence of such organic bases as pyridine
and triethylamine.
in acetonitrile was 83:17, whereas only pyrazole IIId
was isolated when the reaction was carried out in
ethanol.
The ratios of isomeric pyrazoles III and IV formed
in the reactions of aldehyde I with hydrazines IIa–IId
were determined from the 1H NMR spectra of the reac-
tion mixtures. The spectra clearly displayed doublets
from protons in the pyrazole rings of III and IV with
characteristic coupling constants [19], and the signal
intensities were used to calculate the isomer fractions
(Table 2). As follows from the data in Table 2, the
reactions of compound I with hydrazines IIa–IId are
regioselective, and the major products are the corre-
sponding 1,5-disubstituted pyrazole derivatives IIIa–
IIId. Electron-donating substituents in the hydrazine
molecule favor formation of 1,3-disubstituted pyra-
zoles IV. A probable mechanism is illustrated by
Scheme 4. The condensation of hydrazine II with alde-
hyde I may be followed by cyclization of the hydra-
zone thus formed via conjugate addition–elimination
(path a) or initial addition–elimination may be fol-
lowed by cyclization or condensation of intermediate
hydrazino-substituted enones (paths b and c).
In the 1H NMR spectra of hydrazones IXa and IXb,
signals from the olefinic protons appeared as doublets
at δ 6.42 and 8.14 ppm and 6.47 and 8.85 ppm, respec-
3
tively, with a coupling constant J of 9.1 Hz. The mo-
lecular ion peaks in the mass spectra of IXa and IXb
had intensities of 58.5 and 100%, respectively. Hydra-
zone IXc was isolated in 81% yield in the reaction of
aldehyde I with 4-bromophenylhydrazine in boiling
acetonitrile (reaction time 2 h). Prolonged heating of
the reactants in boiling ethanol or acetonitrile gave
pyrazole IIIc. The ratio of isomeric pyrazoles IIId and
IVd formed in the reaction of I with methylhydrazine
We continued our search for optimal conditions for
the selective formation of 1,3-disubstituted pyrazoles
by carrying out the reaction of aldehyde I with phenyl-
hydrazine in the presence of 1,4-diazabicyclo[2.2.2]-
octane (DABCO) which should favor the reaction to
follow path b [20]. However, in this case the product
was a mixture of pyrazoles IIIa and IVa with in-
Scheme 3.
H
Me
N
H
Me
N
N
NH2
R
I
+
R
O
Me
N
H
EtO
IXa–IXc
R = 4-O2N (a), 2,4-(O2N)2 (b), 4-Br (c).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 4 2009

REACTION OF ETHYL 4-[(E)-1-CHLORO-3-OXOPROP-1-EN-1-YL]-...
567
Scheme 4.
NHR
N
a
H
N
H
Ht
–HCl
–H2O
–H2O
–H2O
N
R
Ht
Cl
Ht
Me
O
H
b
H
H
O
+
RNHNH2
Ht =
N
H
O
–HCl
H
Me
N
N
N
H
Ht
Cl
Ht
N
H
R
EtO
R
I
II
H
c
H
N
O
Ht
–HCl
N
NH2
Ht
N
R
R
Scheme 5.
NMe2
R
N
N
Cl
N
Me
Me
N
Me
N
2Me2NNH2
Et2O
RNHNH2 (IIa–IId)
R
I
+
O
O
O
Me
Me
Me
N
N
H
N
H
H
EtO
EtO
EtO
X
IIIa–IIId
IVa–IVd
R = Ph (a), 4-MeC6H4 (b), 4-BrC6H4 (c), Me (d).
creased fraction of the latter (22%). Increase in the
fraction of 1,3-disubstituted pyrazole was also observed
when aldehyde I was replaced by its N,N-dimethylhy-
drazone X in the reaction with hydrazines IIa–IId
(Scheme 5). Taking into account that hydrazide ion is
a difficultly departing group as compared to hydroxide
ion, the reaction was expected to begin with addition
of hydrazine at the double C=C bond with subsequent
elimination of hydrogen chloride and cyclization with
liberation of dimethylhydrazine. Equimolar amounts of
hydrazone X and the corresponding hydrazine were
heated for 60 h at 75°C in appropriate solvent, the
solvent and N,N-dimethylhydrazine were removed, and
The only product isolated in the reaction of alde-
hyde I with hydrazine hydrate was 3(5)-substituted
pyrazole XI (Scheme 6). Compound XI in DMSO-d6
displayed in the 1H NMR spectrum (500 MHz, 298 K)
two broadened singlets at δ 6.23 and 7.62 ppm instead
of characteristic doublets. This pattern may be inter-
preted in terms of dynamic equilibrium between tauto-
meric pyrazoles in solution.
Thus, the reactions of ethyl 4-[(E)-1-chloro-3-oxo-
prop-1-en-1-yl]-3,5-dimethyl-1H-pyrrole-2-carbox-
Table 3. Reaction of hydrazone X with hydrazines IIa–IId
in ethanol and acetonitrile
1
the residue was analyzed by H NMR. The results are
Ratio III:IV
given in Table 3. In fact, the fraction of 1,3-disubsti-
tuted pyrazole increased when the reaction was per-
formed in ethanol, especially with methylhydrazine.
The reactions in acetonitrile resulted in the formation
of only 1,5-disubstituted pyrazoles, their 1,3-disubsti-
tuted isomers were not detected, and reaction mixtures
contained unreacted hydrazone X.
Hydrazine
ethanol
acetonitrile
IIa
IIb
IIc
IId
85:15
87:13
90:10
67:33
41:59
42:58
45:55
70:30
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 4 2009

MIKHED’KINA et al.
568
Scheme 6.
N
NH
N2H4 ·H2O
NaOAc
Me
NH
Me
N
I
O
O
Me
Me
N
N
H
H
EtO
EtO
XI
ylate (I) with hydrazines in both acidic and basic
media give the corresponding 1,5-disubstituted pyra-
zoles as the major products. The formation of 1,3-di-
substituted isomers is favored by aprotic solvents and
the presence of a sterically hindered base capable of
forming hydrazide ion in the first step.
Ethyl 3,5-dimethyl-4-[1-(4-methylphenyl)-1H-
pyrazol-5-yl]-1H-pyrrole-2-carboxylate (IIIb). Sol-
vent ethanol, reaction time 4 h. Yield 0.17 g (53%),
mp 172°C. IR spectrum, ν, cm–1: 3312 (NH), 1664
(C=O), 1600, 1512, 1432, 1384, 1280, 1224, 1136,
1
1104, 1024, 960, 832, 784. H NMR spectrum
(DMSO-d6), δ, ppm: 1.26 t (3H, CH2CH3, J = 7.1 Hz),
1.85 s (3H, 3-CH3), 1.90 s (3H, 5-CH3), 2.29 s (3H,
CH3), 4.19 q (2H, OCH2, J = 7.1 Hz), 6.38 d (1H, 4′-H,
J = 1.8 Hz), 7.05–7.22 m (4H, C6H4), 7.72 d (1H, 3′-H,
J = 1.8 Hz), 11.51 s (1H, 1-H). Mass spectrum:
m/z 323 [M]+. Found, %: C 70.68; H 6.64; N 13.04.
C19H21N3O2. Calculated, %: C 70.57; H 6.55; N 12.99.
M 323.39.
EXPERIMENTAL
1
The H NMR spectra were recorded on Varian
Mercury VX-200 (200 MHz) and Bruker Avance
DRX-500 (500 MHz) spectrometers using tetramethyl-
silane as internal standard. The IR spectra were meas-
ured in KBr on a Specord M-80 instrument. The mass
spectra (electron impact, 70 eV) were obtained on
a Varian 1200L mass spectrometer with direct sample
admission into the ion source. The progress of reac-
tions was monitored by TLC on Silufol UV-254 plates
using chloroform–ethyl acetate (7:3) as eluent.
Ethyl 4-[1-(4-bromophenyl)-1H-pyrazol-5-yl]-
3,5-dimethyl-1H-pyrrole-2-carboxylate (IIIc). Sol-
vent ethanol, reaction time 6 h. Yield 0.33 g (85%),
mp 170–171°C. IR spectrum, ν, cm–1: 3304 (NH),
1664 (C=O), 1488, 1440, 1376, 1280, 1136, 1104,
1
Reaction of ethyl 4-[(E)-1-chloro-3-oxoprop-1-
en-1-yl]-3,5-dimethyl-1H-pyrrole-2-carboxylate (I)
with hydrazines IIa–IId (general procedure). A mix-
ture of 1 mmol (0.26 g) of aldehyde I and 1 mmol of
hydrazine IIa–IId in the corresponding solvent was
heated under reflux until the initial compound disap-
peared (TLC). The mixture was evaporated under re-
duced pressure, and the residue was recrystallized from
methylene chloride. The isomer ratio was determined
from the 1H NMR spectrum of the residue.
1024, 1008, 960, 832, 776. H NMR spectrum
(DMSO-d6), δ, ppm: 1.27 t (3H, CH2CH3, J = 7.1 Hz),
1.87 s (3H, 3-CH3), 1.90 s (3H, 5-CH3), 4.20 q (2H,
OCH2, J = 7.1 Hz), 6.43 d (1H, 4′-H, J = 1.8 Hz),
7.14–7.64 m (4H, C6H4), 7.77 d (1H, 3′-H, J = 1.8 Hz),
11.59 s (1H, 1-H). Mass spectrum: m/z 389/387 [M]+.
Found, %: C 55.76; H 4.76; N 10.87.C18H18BrN3O2.
Calculated, %: C 55.68; H 4.67; N 10.82. M 388.26.
Ethyl 3,5-dimethyl-4-(1-methyl-1H-pyrazol-5-
yl)-1H-pyrrole-2-carboxylate (IIId). Solvent ethanol,
reaction time 5 h. Yield 0.12 g (47%), mp 137–138°C.
IR spectrum, ν, cm–1: 3296 (NH), 1656 (C=O), 1560,
1496, 1440, 1376, 1272, 1224, 1200, 1104, 1024, 776.
1H NMR spectrum (DMSO-d6), δ, ppm: 1.29 t (3H,
CH2CH3, J = 7.1 Hz), 2.06 s (6H, 3-CH3, 5-CH3),
3.56 s (3H, NCH3), 4.23 q (2H, OCH2, J = 7.1 Hz),
6.13 d (1H, 4′-H, J = 1.8 Hz), 7.46 d (1H, 3′-H, J =
1.8 Hz), 11.66 s (1H, 1-H). Mass spectrum: m/z 247
[M]+. Found, %: C 63.24; H 7.01; N 17.04. C13H17N3O2.
Calculated, %: C 63.14; H 6.93; N 16.99. M 247.29.
Ethyl 3,5-dimethyl-4-(1-phenyl-1H-pyrazol-5-
yl)-1H-pyrrole-2-carboxylate (IIIa). Solvent ethanol,
reaction time 6 h. Yield 0.22 g (70%), mp 152°C. IR
spectrum, ν, cm–1: 3304 (NH), 1664 (C=O), 1600,
1504, 1440, 1376, 1272, 1208, 1104, 1024, 784, 760,
1
688. H NMR spectrum (DMSO-d6), δ, ppm: 1.26 t
(3H, CH2CH3, J = 7.1 Hz), 1.85 s (3H, 3-CH3), 1.89 s
(3H, 5-CH3), 4.19 q (2H, OCH2, J = 7.1 Hz), 6.41 d
(1H, 4′-H, J = 1.8 Hz), 7.17–7.44 m (5H, C6H5), 7.75 d
(1H, 3′-H, J = 1.8 Hz), 11.54 s (1H, 1-H). Mass spec-
trum: m/z 309 [M]+. Found, %: C 70.00; H 6.27;
N 13.61. C18H19N3O2. Calculated, %: C 69.88; H 6.19;
N 13.58. M 309.36.
Ethyl 3,5-dimethyl-4-[1-(2-phenylhydrazono)-
ethyl]-1H-pyrrole-2-carboxylate (VI). A mixture of
5.31 g (25 mmol) of ethyl 4-acetyl-3,5-dimethyl-1H-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 4 2009

REACTION OF ETHYL 4-[(E)-1-CHLORO-3-OXOPROP-1-EN-1-YL]-...
569
pyrrole-2-carboxylate (V), 2.80 g (25 mmol) of phen-
ylhydrazine (IIa), and 0.61 g (7.6 mmol) of polyphos-
phoric acid in 74 ml of anhydrous alcohol was heated
for 40 h under reflux. The precipitate was filtered off
and washed on a filter with water and ethanol. Yield
6.23 g (82%), mp 176°C (from EtOH). IR spectrum, ν,
cm–1: 3296 (NH), 1664 (C=O), 1600, 1488, 1504,
1432, 1264, 1208, 1128, 1096, 1064, 1024, 776, 760.
1H NMR spectrum (DMSO-d6), δ, ppm: 1.29 t (3H,
CH2CH3, J = 7.1 Hz), 2.15 s (3H, CH3), 2.29 s (3H,
3-CH3), 2.34 s (3H, 5-CH3), 4.22 q (2H, OCH2, J =
7.1 Hz), 6.61–7.21 m (5H, C6H5), 8.86 s (1H, NH),
11.32 s (1H, 1-H). Mass spectrum: m/z 299 [M]+.
Found, %: C 68.29; H 7.18; N 14.13. C17H21N3O2. Cal-
culated, %: C 68.20; H 7.07; N 14.04. M 299.37.
trum, ν, cm–1: 3296 (NH), 2550–3100 (OH), 1672,
1656 (C=O), 1600, 1520, 1504, 1440, 1280, 1200,
1
1104, 752, 688. H NMR spectrum (DMSO-d6), δ,
ppm: 1.30 t (3H, CH2CH3, J = 7.1 Hz), 2.13 s (3H,
4′-CH3), 2.15 s (3H, 2′-CH3), 4.24 q (2H, OCH2, J =
7.1 Hz), 7.13–8.02 m (5H, C6H5), 9.04 s (1H, 5-H),
11.45 s (1H, 1′-H), 12.36 s (1H, COOH). Mass spec-
trum: m/z 353 [M]+. Found, %: C 64.48; H 5.52;
N 11.96. C19H19N3O4. Calculated, %: C 64.58; H 5.42;
N 11.89. M 353.37.
Ethyl 3,5-dimethyl-4-(1-phenyl-1H-pyrazol-3-
yl)-1H-pyrrole-2-carboxylate (IVa). Copper powder,
1.81 g (29 mmol), was added to a solution of 1.27 g
(4 mmol) of carboxylic acid VIII in 14 ml of quino-
line, and the mixture was heated for 3 h under reflux. It
was then cooled, 25 ml of diethyl ether was added, and
the copper powder was filtered off and washed with
diethyl ether on a filter. The filtrate was evaporated to
dryness under reduced pressure, and the residue was
recrystallized from toluene. Yield 0.88 g (79%),
mp 184°C. IR spectrum, ν, cm–1: 3288 (NH), 1656
(C=O), 1600, 1504, 1432, 1344, 1280, 1256, 1208,
Ethyl 4-(4-formyl-1-phenyl-1H-pyrazol-3-yl)-
3,5-dimethyl-1H-pyrrole-2-carboxylate (VII). Di-
methylformamide, 10 ml, was cooled to 0°C, and
6.14 g (40 mmol) of phosphoryl chloride was added
under stirring at such a rate that the temperature did
not exceed 10°C. The mixture was stirred for 30 min,
and a solution of 5.98 g (20 mmol) of phenylhydrazone
VI in 10 ml of DMF was added under stirring, main-
taining the temperature below 10°C. The mixture was
stirred for 1 h, heated to 60°C, and kept for 3 h at that
temperature. It was then cooled, poured onto 30 g of
ice, and neutralized to pH 7 with sodium acetate. The
precipitate was filtered off and washed on a filter with
water and ethanol. Yield 6.06 g (90%), mp 188°C
(from EtOH). IR spectrum, ν, cm–1: 3312 (NH), 1680,
1664 (C=O), 1660, 1544, 1504, 1432, 1280, 1224,
1
1120, 1048, 776, 752, 688. H NMR spectrum
(DMSO-d6), δ, ppm: 1.29 t (3H, CH2CH3, J = 7.1 Hz),
2.38 s (3H, 3-CH3), 2.44 s (3H, 5-CH3), 4.23 q (2H,
OCH2, J = 7.1 Hz), 6.60 d (1H, 4′-H, J = 2.6 Hz),
7.20–7.91 m (5H, C6H5), 8.52 d (1H, 5′-H, J = 2.6 Hz),
11.46 s (1H, 1-H). Mass spectrum: m/z 309 [M]+.
Found, %: C 70.02; H 6.26; N 13.62. C18H19N3O2. Cal-
culated, %: C 69.88; H 6.19; N 13.58. M 309.36.
Ethyl 4-{1-chloro-3-[2-(4-nitrophenyl)hydra-
zono]prop-1-en-1-yl}-3,5-dimethyl-1H-pyrrole-2-
carboxylate (IXa). A mixture of 0.26 g (1 mmol) of
aldehyde I and 0.15 g (1 mmol) of 4-nitrophenyl-
hydrazine in 10 ml of ethanol was heated for 2 h under
reflux. The precipitate was filtered off and washed
with ethanol on a filter. Yield 0.33 g (84%), mp 213°C.
IR spectrum, ν, cm–1: 3288 (NH), 1680 (C=O), 1600,
1576, 1504, 1480, 1440, 1296, 1272, 1192, 1112, 832,
1
1104, 1024, 752, 688. H NMR spectrum (DMSO-d6),
δ, ppm: 1.30 t (3H, CH2CH3, J = 7.1 Hz), 2.19 s (3H,
3-CH3), 2.21 s (3H, 5-CH3), 4.25 q (2H, OCH2, J =
7.1 Hz), 7.35–8.05 m (5H, C6H5), 9.27 s (1H, 5′-H),
9.71 s (1H, CHO), 11.66 s (1H, 1-H). Mass spectrum:
m/z 337 [M]+. Found, %: C 67.59; H 5.78; N 12.53.
C19H19N3O3. Calculated, %: C 67.64; H 5.68; N 12.46.
M 337.37.
1
752. H NMR spectrum (DMSO-d6), δ, ppm: 1.29 t
3-(5-Ethoxycarbonyl-2,4-dimethyl-1H-pyrrol-3-
yl)-1-phenyl-1H-pyrazole-4-carboxylic acid (VIII).
Aldehyde VII, 3.37 g (10 mmol), was dispersed in
10 ml of 50% aqueous pyridine, and 1.58 g (10 mmol)
of potassium permanganate was added in portions over
a period of 1 h under stirring and cooling, maintaining
the temperature at 20–22°C. The mixture was stirred
for 4 h, the precipitate of manganese dioxide was fil-
tered off, and the filtrate was neutralized to pH 7 with
dilute hydrochloric acid. The precipitate was filtered
off and washed on a filter with water and ethanol.
Yield 2.30 g (65%), mp 223°C (from EtOH). IR spec-
(3H, CH2CH3, J = 7.1 Hz), 2.26 s (3H, 3-CH3), 2.29 s
(3H, 5-CH3), 4.24 q (2H, OCH2, J = 7.1 Hz), 6.42 d
(1H, =CH, J = 9.1 Hz), 7.04–7.13 d and 8.08–8.16 d
(2H each, C6H4), 8.14 d (1H, =CH, J = 9.1 Hz), 11.44 s
(1H, NH), 11.70 s (1H, NH). Mass spectrum:
m/z 392/390 [M]+. Found, %: C 55.24; H 5.00;
N 14.24. C18H19ClN4O4. Calculated, %: C 55.32;
H 4.90; N 14.34. M 390.82.
Ethyl 4-{1-chloro-3-[2-(2,4-dinitrophenyl)hydra-
zono]prop-1-en-1-yl}-3,5-dimethyl-1H-pyrrole-2-
carboxylate (IXb). A solution of 0.26 g (1 mmol) of
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MIKHED’KINA et al.
570
aldehyde I in 5 ml of ethanol was added to a solution
of 0.20 g (1 mmol) of 2,4-dinitrophenylhydrazine in
a mixture of 5 ml of ethanol, 1.5 ml of water, and 1 ml
of sulfuric acid. The mixture was heated for 15 min
under reflux, and the precipitate was filtered off and
washed on a filter with water and ethanol. Yield 0.42 g
(96%), mp 229–230°C. IR spectrum, ν, cm–1: 3288
(NH), 1680 (C=O), 1623, 1608, 1560, 1512, 1424,
1336, 1320, 1280, 1136, 1096, 1024, 832, 744.
1H NMR spectrum (DMSO-d6), δ, ppm: 1.29 t (3H,
CH2CH3, J = 7.1 Hz), 2.28 s (3H, 3-CH3), 2.30 s (3H,
5-CH3), 4.23 q (2H, OCH2, J = 7.1 Hz), 6.47 d (1H,
=CH, J = 9.1 Hz), 7.88 d (1H, 6′-H, J = 9.7 Hz),
8.36 d.d (1H, 5′-H, J = 9.7, 2.7 Hz), 8.84 d (1H, 3′-H,
J = 2.7 Hz), 8.85 d (1H, =CH, J = 9.1 Hz), 11.73 s and
11.79 s (1H each, NH). Mass spectrum: m/z 437/435
[M]+. Found, %: C 49.55; H 4.25; N 15.98.
C18H18ClN5O6. Calculated, %: C 49.61; H 4.16;
N 16.07. M 435.82.
Ethyl 4-[1-chloro-3-(2,2-dimethylhydrazono)-
prop-1-en-1-yl]-3,5-dimethyl-1H-pyrrole-2-carbox-
ylate (X). A solution of 1.51 g (6 mmol) of aldehyde I
and 0.9 ml (12 mmol) of N,N-dimethylhydrazine in
30 ml of diethyl ether was stirred for 48 h at room tem-
perature. The mixture was evaporated, and the residue
was washed with water and recrystallized from etha-
nol. Yield 1.13 g (64%), mp 134–135°C. IR spectrum,
ν, cm–1: 3272 (NH), 1672 (C=O), 1536, 1504, 1440,
1384, 1352, 1288, 1200, 1104, 1048, 1024, 872, 776.
1H NMR spectrum (DMSO-d6), δ, ppm: 1.28 t (3H,
CH2CH3, J = 7.1 Hz), 2.20 s (3H, 3-CH3), 2.24 s (3H,
5-CH3), 2.91 s (6H, NCH3), 4.22 q (2H, OCH2, J =
7.1 Hz), 6.24 d (1H, =CH, J = 8.6 Hz), 7.13 d (1H,
=CH, J = 8.6 Hz), 11.55 s (1H, 1-H). Mass spectrum:
m/z 299/297 [M]+. Found, %: C 56.42; H 6.86;
N 14.02. C14H20ClN3O2. Calculated, %: C 56.47;
H 6.77; N 14.11. M 297.78.
Ethyl 3,5-dimethyl-4-[1H-pyrazol-3(5)-yl]-1H-
pyrrole-2-carboxylate (XI). A mixture of 0.52 g
(2 mmol) of aldehyde I, 0.33 g (4 mmol) of sodium
acetate, and 0.6 ml (12 mmol) of hydrazine hydrate in
10 ml of ethanol was heated for 10 h under reflux. The
mixture was evaporated under reduced pressure, and
the residue was washed with water and recrystallized
from ethanol. Yield 0.44 g (95%), mp 158°C. IR spec-
trum, ν, cm–1: 3288 (NH), 1656 (C=O), 1600, 1512,
Ethyl 4-{3-[2-(4-bromophenyl)hydrazono]-1-
chloroprop-1-en-1-yl}-3,5-dimethyl-1H-pyrrole-2-
carboxylate (IXc). A solution of 0.26 g (1 mmol) of
aldehyde I and 0.19 g (1 mmol) of 4-bromophenyl-
hydrazine (IIc) in 10 ml of acetonitrile was heated for
2 h under reflux. The mixture was cooled, and the
precipitate was filtered off and washed on a filter with
ethanol. Yield 0.34 g (81%), mp 144°C (from EtOH).
IR spectrum, ν, cm–1: 3304 (NH), 1672 (C=O), 1616,
1592, 1568, 1512, 1480, 1440, 1288, 1256, 1192,
1
1440, 1280, 1208, 1096, 928, 776. H NMR spectrum
(DMSO-d6), δ, ppm: 1.29 t (3H, CH2CH3, J = 7.1 Hz),
2.25 s (3H, 3-CH3), 2.30 s (3H, 5-CH3), 4.22 q (2H,
OCH2, J = 7.1 Hz), 6.22 s and 7.62 s (1H each, 4′-H,
5′-H), 11.43 s (1H, 1-H), 12.64 s (1H, 1′-H). Mass
spectrum: m/z 233 [M]+. Found, %: C 61.90; H 6.56;
N 18.05. C12H15N3O2. Calculated, %: C 61.79; H 6.48;
N 18.01. M 233.27.
1
1168, 1136, 1096, 1024, 856, 808. H NMR spectrum
(DMSO-d6), δ, ppm: 1.29 t (3H, CH2CH3, J = 7.1 Hz),
2.24 s (3H, 3-CH3), 2.27 s (3H, 5-CH3), 4.23 q (2H,
OCH2, J = 7.1 Hz), 6.34 d (1H, =CH, J = 9.1 Hz),
6.88–7.40 m (4H, C6H4), 7.96 d (1H, =CH, J = 9.1 Hz),
10.68 s and 11.61 s (1H each, NH). Mass spectrum:
m/z 425/423 [M]+. Found, %: C 50.81; H 4.60; N 9.81.
C18H19BrClN3O2. Calculated, %: C 50.90; H 4.51;
N 9.89. M 424.72.
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