Synthesis of 4-[(p-alkylanilino-p-alkylphenyl)methyl]-4-butyl-1,2- diphenylpyrazolidine-3,5-diones

Article abstract of DOI:10.1134/S1070363206020241

4-Butyl-1,2-diphenylpyrazolidine-3,5-dione derivatives were prepared by its condensation with Schiff bases formed from p-aminobenzoic acid and its methyl and ethyl esters as amine components and substituted aromatic aldehydes. Pleiades Publishing, Inc., 2006.

Full text of DOI:10.1134/S1070363206020241

ISSN 1070-3632, Russian Journal of General Chemistry, 2006, Vol. 76, No. 2, pp. 307 310.
Pleiades Publishing, Inc., 2006.
Original Russian Text
pp. 324 327.
N.G. Kozlov, S.V. Rubis, A.V. Tkachev, L.I. Basalaeva, 2006, published in Zhurnal Obshchei Khimii, 2006, Vol. 76, No. 2,
Synthesis of 4-[(p-Alkylanilino-p-alkylphenyl)methyl]-
4-butyl-1,2-diphenylpyrazolidine-3,5-diones
N. G. Kozlov*, S. V. Rubis*, A. V. Tkachev**, and L. I. Basalaeva*
* Institute of Physical Organic Chemistry, Belarussian National Academy of Sciences,
ul. Surganova 13, Minsk, 220072 Belarus
e-mail: loc@ifoch.bas-net.by
** Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division,
Russian Academy of Sciences, Novosibirsk, Russia
Received February 9, 2005
Abstract 4-Butyl-1,2-diphenylpyrazolidine-3,5-dione derivatives were prepared by its condensation with
Schiff bases formed from p-aminobenzoic acid and its methyl and ethyl esters as amine components and
substituted aromatic aldehydes.
DOI: 10.1134/S1070363206020241
Azomethines containing a readily polarizable C=N
bond add to organic compounds containing labile
hydrogen atoms [1 3]. 4-Butyl-1,2-diphenylpyrazoli-
dine-3,5-dione (phenylbutazone) as a CH acid is
among such compounds.
methine, followed by the electron redistribution. The
reaction is favored by the polarizability of the C=N
bond in Schiff bases and formation of a chelate bond
of the enol hydrogen atom with the azomethine nitro-
gen atom.
The polarizability of the azomethine bond in Schiff
bases is influenced by the nature and location of sub-
stituents in the benzene rings of the aniline and benz-
aldehyde fragments. The electron-withdrawing substit-
uents in the p-position enhance the polarization of the
azomethine bond, and condensation with Schiff bases
containing these substituents occurs under milder con-
ditions without additional heating, with high yields of
the final products. In particular, 4-butyl-1,2-diphenyl-
4-[(p-ethoxyanilino-p-bromophenyl)methyl]pyrazoli-
dine-3,5-dione Vj is formed within 15 min in 80%
yield, and 4-butyl-1,2-diphenyl-4-[(p-ethoxyanilino-
p-hydroxyphenyl)methyl]pyrazolidine-3,5-dione Vl,
in 32% yield after refluxing the reactants (IIIl, IV) for
no less than 40 min. If the benzaldehyde fragment of
the azomethine contains substituents (both donor and
acceptor) in the o-position (IIIm, IIIn), chelate A is
not formed, and addition of phenylbutazone IV does
not occur at all, apparently because of the steric effect
of the substituent.
Reactions of azomethines with phenylbutazone are
of not only basic but also applied importance, as their
products may exhibit biological activity, taking into
account the fact that phenylbutazone is a structural
analog of amidopyrine, an analgetic, antipyretic, and
antiphlogistic. Phenylbutazone considerably surpasses
amidopyrine in the antiphlogistic activity and is there-
fore considered as a nonsteroid antiphlogistic [4, 5].
In this study we performed condensation of phenyl-
butazone IV with Schiff bases III derived from benz-
aldehyde derivatives IIa IIf and amines containing
pharmacophore groups: p-aminobenzoic acid Ia and
its methyl (Ib) and ethyl (Ic) esters. It is known that
p-aminobenzoic acid is a microbial growth factor [6],
and ethyl p-aminobenzoate hydrochloride (Anesthe-
sin) exhibits an anesthetic effect and is used for local
anesthesia as cocaine substitute [7].
The reactions were performed by refluxing the
reactants in alcohol for 15 40 min.
The yields, melting points, and elemental analyses
of 4-butyl-1,2-diphenylpyrazolidine-3,5-dione deriva-
tives Va Vl are listed in Table 1.
Phenylbutazone IV is a pyrazolidine derivative.
It exists in solution as a mixture of the enol and dicar-
bonyl tautomers [8].
1
The structures of Va Vl were confirmed by H
The mechanism of reactions of phenylbutazone IV
with Schiff bases III presumably involves formation
of complex A between the enol form of IV and azo-
NMR and IR spectroscopy and by mass spectrometry.
The IR spectra contained bands characteristic of the
carbonyl groups of the diketone moiety (a band at
307

308
KOZLOV et al.
R
R
+
R
N CH
R
NH2
OHC
Ia Ic
IIa IIf
IIIa IIIn
R
R
HN
H
R
R
N
O
O
CH
N
H
O
CH
O
N
N
O
+
O
N
N
N
IV
A
Va Vl
R = 4-COOH (a), 4-CH3OCO (Ib), 4-C2H5OCO (Ic); R = H (IIa), 4-Br (IIb), 4-NO2 (IIc), 4-OH (IId), 2-Cl (IIe),
2-OH (IIf); R = 4-COOH, R = H (IIIa, Va), 4-Br (IIIb, Vb), 4-NO2 (IIIc, Vc), 4-OH (IIId, Vd), 2-Cl (IIIm), 2-OH
(IIIn); R = 4-CH3OCO, R = H (IIIe, Ve), 4-Br (IIIf, Vf), 4-NO2 (IIIg, Vg), 4-OH (IIIh, Vh); R = 4-C2H5OCO, R = H
(IIIi, Vi), 4-Br (IIIj, Vj), 4-NO2 (IIIk, Vk), 4-OH (IIIl, Vl).
1
1703 1710 cm ) and of the ester fragment (a band
CH2 groups in the butyl substituent, respectively. The
1
at 1726 1748 cm in the spectra of Ve Vl). The
carbonyl group of the carboxylate ion [C6H5CO2] in
Va Vd absorbs at 1605 1603 cm . The spectra of
Ve Vl contain a band at 1280 1270 cm characteris-
spectra of Vb, Vf, and Vj also contain a strong band
1
at 570 550 cm assignable to the C Br stretching
1
vibrations, and the spectra of Vc, Vg, and Vk, bands
1
1
at 1350 and 1520 cm belonging to the symmetric
tic of the C O C stretching vibrations. The presence
of the secondary amino group in all the compounds
and antisymmetric vibrations of the N O bonds, re-
spectively.
1
Va Vl is confirmed by a band at 3390 3360 cm .
The bands at 2950 2930 and 2870 2850 cm 1 belong
to the antisymmetric and symmetric vibrations of the
The mass spectra of Va Vl contain no molecular
peak (M+). The strongest (100%) fragment peak, m/z
Table 1. Yields, melting points, and elemental analyses of 4-[(R-anilino-R -phenyl)methyl]-4-butyl-1,2-diphenylpyrazol-
idine-3,5-diones Va Vl
Found, %
Calculated, %
Comp.
no.
Yield,
%
mp,
C
Formula
C
H
N (Hlg)
7.88
C
H
N (Hlg)
Va
Vb
Vc
Vd
Ve
Vf
Vg
Vh
Vi
77
80
52
45
70
76
60
40
60
80
50
32
177a
229 230
247
74.24
64.52
68.53
72.10
74.62
65.21
68.90
72.49
74.85
65.64
69.34
72.85
5.83
C33H31N3O4
C33H30BrN3O4
C33H30N4O6
C33H31N3O5
C34H33N3O4
C34H32BrN3O4
C34H32N4O6
C34H33N3O5
C35H35N3O4
C35H34BrN3O4
C35H34N4O6
C35H35N3O5
74.28
64.71
68.50
72.11
74.57
65.18
68.91
72.45
74.84
65.63
69.29
72.77
5.82
4.94
5.23
5.68
6.07
5.15
5.44
5.90
6.28
5.35
5.65
6.11
7.87
6.86 (13.05)
9.68
7.65
7.67
6.71 (12.75)
9.45
7.45
7.48
6.56 (12.47)
9.24
4.91
5.20
5.70
6.06
5.09
5.38
5.90
6.27
5.39
5.59
6.15
6.89 (13.00)
9.61
136
7.63
7.71
131a
138a
158
6.70 (12.78)
9.42
172
7.48
7.53
121a
138a
123
Vj
Vk
Vl
6.60 (12.28)
9.27
138
7.28
7.27
a
The melting points agree with the published data for Va [9] and Ve, Vf, Vj [10].
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 2 2006

SYNTHESIS OF 4-[(p-ALKYLANILINO-p-ALKYLPHENYL)METHYL]-...
309
1
Table 2. H NMR spectra of 4-[(R-anilino-R -phenyl)methyl]-4-butyl-1,2-diphenylpyrazolidine-3,5-diones Va Vl, , ppm
(J, Hz) (2 5% solutions in DMSO-d6)
Comp.
no.
CH, d
CH2,
m
CH2CH2, CH3, OCH3,
Aromatic protons, protons of R and R ,
and NH protons
(3J)
m
t
s
Va
Vb
Vc
Vd
5.00 (6.0)
1.95
1.25 1.49 0.90
6.50 6.55 m, 6.75 d (9.0), 6.85 d (8.0), 6.90 d (8.8), 7.10
7.40 m, 7.50 7.70 m, 7.90 8.00 m, 10.00 s (1H, NH),
12.00 br.s (1H, COOH)
5.90 d (8.7), 6.29 d (8.5), 6.50 d (9.0), 6.60 d (9.2), 6.84
7.00 m, 7.06 7.10 m, 7.48 7.55 m, 8.20 s (1H, NH), 9.70
(1H, COOH)
6.50 d (8.0), 6.60 d (9.0), 6.90 d (8.0), 7.00 d (10.0), 7.05
7.20 m, 7.65 m, 8.05 m, 8.10 8.20 m, 8.30 d (9.0), 8.40 d
(7.6), 10.20 s (1H, NH), 11.50 br.s (1H, COOH)
6.30 6.50 m, 6.70 d (9.0), 6.85 d (8.9), 6.93 d (8.5), 7.00
7.30 m, 7.60 7.80 m, 7.95 8.10 m, 10.10 s (1H, NH),
12.20 s (1H, OH), 12.80 s (1H, COOH)
4.75 (6.3) 1.85 1.95 1.18 1.35 0.88
5.15 (6.0)
1.95
1.20 1.25 0.95
4.90 (5.9) 1.95 2.10 1.25 1.50 0.93
Ve
Vf
4.95 (6.0) 1.90 2.05 1.15 1.20 0.96
4.85 (6.2) 1.90 2.10 1.20 1.30 0.87
5.10 (5.9) 1.90 2.00 1.32 1.50 0.98
5.00 (6.1) 1.95 2.10 1.15 1.35 1.05
3.70 6.20 6.40 m, 6.50 d (8.5), 6.65 d (9.3), 6.79 d (9.0), 7.65 d
(9.0), 7.80 8.00 m, 10.00 s (1H, NH)
3.68 6.10 d (8.9), 6.48 d (8.5), 6.70 d (9.0), 6.79 d (9.2), 7.00
7.25 m, 7.69 d (6.9), 9.90 s (1H, NH)
3.72 6.55 d (8.5), 6.70 d (8.9), 6.90 d (9.0), 7.10 7.30 m, 7.60
7.70 m, 8.05 8.25 m, 8.35 8.40 m, 10.18 s (1H, NH)
3.62 6.20 d (8.0), 6.30 d (8.7), 6.80 d (8.9), 7.05 7.20 m, 7.40
7.50 m, 7.90 8.00 m, 10.50 s (1H, NH), 11.60 s (1H, OH)
6.40 d (9.0), 6.56 d (8.9), 6.67 d (9.3), 6.76 d (8.6), 6.85 d
(8.3), 7.10 7.30 m, 7.40 7.50 m, 7.70 d (8.9), 7.90 d (8.3),
8.10 d (10.2), 8.50 s, 10.00 s (1H, NH)
Vg
Vh
Via 4.80 (6.0) 1.80 2.00 1.25 1.26 0.95
Vjb 4.90 (6.8) 1.90 2.10 1.26 1.40 0.80
6.40 d (10.0), 6.65 d (9.0), 6.80 d (9.2), 6.90 d (9.6), 7.15
7.30 m, 7.65 d (9.2), 7.90 d (9.0), 8.00 d (9.3), 9.80 s (1H,
NH)
6.50 d (10.0), 6.55 d (10.4), 6.70 d (10.0), 6.90 d (9.7),
7.00 d (10.5) 7.05 7.20 m, 7.30 7.35 m, 8.00 m, 8.10 m,
8.15 8.20 m, 10.20 s (1H, NH)
6.50 d (9.7), 6.70 d (9.0), 6.85 d (9.6), 6.95 d (9.3), 7.10
7.25 m, 7.60 7.70 m, 7.90 d (8.9), 8.00 d (9.0), 10.10 s (1H,
NH), 11.60 s (1H, OH)
Vkc 5.16 (6.4)
Vld 4.95 (7.0)
1.90
1.96
1.15 1.20 0.90
1.16 1.25 0.85
a
b
c
, ppm: 4.35 q (OCH CH ), 1.40 t (OCH CH ).
, ppm: 4.20 q (OCH CH ), 1.40 t (OCH CH ).
, ppm: 4.18 q (OCH CH ),
2 3
2
3
2
3
2
3
2
3
d
1.45 t (OCH CH ).
, ppm: 4.35 q (OCH CH ), 1.47 t (OCH CH ).
2
3
2 3 2 3
77, corresponds to the [C6H5]+ ions; the other major
peaks are m/z 308 (22 36%), phenylbutazone ion, and
m/z 183 (43 72%), [C6H5CHNHC6H5]+ ion.
quartet at 4.18 4.35 ppm (OCH2) and a triplet at
1.40 1.49 ppm (CH3).
EXPERIMENTAL
1
The H NMR spectra of Va Vl (Table 2) contain
signals of the butyl substituent, namely, triplet of the
terminal CH3 group (0.80 1.05 ppm), multiplet of
two CH2 groups at 1.15 1.50 ppm, and multiplet at
1.80 2.10 ppm of the -CH2 group. 4-Butyl-4-[(p-
methoxyanilino-p-alkylphenyl)methyl]-1,2-diphenyl-
pyrazolidine-3,5-diones Ve Vh exhibit a singlet at
3.62 3.72 ppm belonging to three protons of the
OCH3 group; the ethoxy group in Vi Vl gives a
The IR spectra were recorded on a Nicolet Protégé-
460 spectrometer. The H NMR spectra were meas-
1
ured on Bruker DRX-500 (500 MHz) and Tesla BS-
576A (100 MHz) spectrometers. Samples were pre-
pared as 2 5% solutions in DMSO-d6; the chemical
shifts were determined relative to internal TMS. The
mass spectra were taken on a Finnigan MAT-Incos-50
spectrometer (70 eV).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 2 2006

310
KOZLOV et al.
4-Butyl-1,2-diphenylpyrazolidine-3,5-dione (phen-
2. Minbaev, B.U., Shiffovy osnovaniya (Schiff Bases),
ylbutazone) IV was prepared according to [11] from
butyl malonate and hydrazobenzene in alcohol under
the action of sodium metal; mp 105 C. Arylidene-
alkylanilines IIIa IIIn were prepared by reaction of
p-aminobenzoic acid Ia or its methyl (Ib) or ethyl (Ic)
ester with appropriate benzaldehyde IIa IIf, following
the standard procedure [12].
Alma-Ata: Nauka, 1989.
3. Kozlov, N.S., 5,6-Benzokhinoliny (5,6-Benzoquino-
lines), Minsk: Nauka i Tekhnika, 1970.
4. Yavorskii, F.K., Aptechnoe delo (Pharmaceutics),
Moscow: Meditsina, 1959.
5. Ray, S.M. and Lahiri, S.C., J. Indian Chem. Soc.,
4-[( p-Alkylanilino-p-alkylphenyl)methyl]-4-
butyl-1,2-diphenylpyrazolidine-3,5-diones Va Vl.
Arylidenealkylaniline IIIa IIIn (0.001 mol) was dis-
solved in 20 ml of ethanol on heating to 50 60 C.
Then 0.3 g of phenylbutazone was added, and the
mixture was refluxed on a water bath for 15 40 min
until crystals started to form. The precipitate that
formed after cooling was filtered off and recrystallized
from ethanol or ethanol benzene, 2 : 1.
1990, vol. 67, no. 4, p. 324.
6. Belikov, V.G., Farmatsevticheskaya khimiya (Phar-
maceutical Chemistry), Moscow: Vysshaya Shkola,
1985.
7. Lekarstvennye preparaty zarubezhnykh form v Rossii
(Imported Drugs in Russia), Moscow: Russkaya Kniga,
1993, pp. 211, 565.
8. Tsiklicheskie -diketony (Cyclic -Diketones), Va-
nags, G., Ed., Riga: Akad. Nauk Latv. SSR, 1961.
ACKNOWLEDGMENTS
9. Kozlov, N.S. and Krylova, A.I., Uch. Zap. Perm.
Pedagog. Inst., 1967, vol. 34, no. 2, p. 31.
The study was supported by the Belarussian Foun-
dation for Basic Research (project no. Kh04R-017).
10. Kozlov, N.S. and Krylova, A.I., Uch. Zap. Perm.
Pedagog. Inst., 1965, vol. 32, no. 2, p. 57.
REFERENCES
11. Khaletskii, A.M., Pesan, V.R., and Deng Zhun-Xiang,
Zh. Obshch. Khim., 1958, vol. 28, no. 9, p. 2355.
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cheskoi khimii (Course of Theoretical Foundations of
Organic Chemistry), Moscow: Goskhimizdat, 1962.
12. Kozlov, N.G. and Basalaeva, L.I., Zh. Obshch. Khim.,
2001, vol. 71, no. 2, p. 279.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 2 2006