Reaction of antipyrine with Schiff bases

Article abstract of DOI:10.1134/S107036320602023X

New dihydropyrazolone derivatives were prepared by condensation of antipyrine with substituted arylmethyleneanilines or arylmethylene-2- naphthylamines. Pleiades Publishing, Inc., 2006.

Full text of DOI:10.1134/S107036320602023X

ISSN 1070-3632, Russian Journal of General Chemistry, 2006, Vol. 76, No. 2, pp. 302 306.
Pleiades Publishing, Inc., 2006.
Original Russian Text
N.G. Kozlov, L.I. Basalaeva, 2006, published in Zhurnal Obshchei Khimii, 2006, Vol. 76, No. 2, pp. 319 323.
Reaction of Antipyrine with Schiff Bases
N. G. Kozlov 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
Received June 21, 2005
Abstract New dihydropyrazolone derivatives were prepared by condensation of antipyrine with substituted
arylmethyleneanilines or arylmethylene-2-naphthylamines.
DOI: 10.1134/S107036320602023X
1-Phenyl-2,3-dimethylpyrazol-5-one (antipyrine) is
an important pyrazolone derivative and is widely used
for a long time in medicine as antipyretic, analgetic,
and sedative [1, 2]. At present it is one of the main
agents for treatment of diseases characterized by
cyclic progress and pronounced temperature reaction
[3]. The chemical structure of 1-phenyl-2,3-dimethyl-
pyrazol-5-one suggests that one of possible routes to
its new derivatives is the reaction with compounds
containing an azomethine fragment. Such reactions
were examined in this study.
mation of a crystalline precipitate identified as 4-[(1,5-
dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-
yl)(4-alkylphenyl)methyl]-1,5-dimethyl-2-phenyl-1,2-
dihydro-3H-pyrazol-3-one IVa or IVb, i.e., presuma-
bly, at elevated temperatures in an acidic medium azo-
methines IId, IIe, IIi, IIj, IIn, IIo, IIs, and IIt
undergo hydramine cleavage. The aldehyde released
in the process reacts with two antipyrine molecules
along pathway 2. The corresponding benzaldehydes
were steam-distilled from the remaining solution and
identified as phenylhydrazones. After neutralization of
the acidic solution with an alkali, p-aminobenzoic acid
or its esters are separated out, and antipyrine is re-
covered from the residue according to [4].
We studied the reactions of antipyrine I with Schiff
bases IIa IIt derived from p-aminobenzoic acid, its
methyl and ethyl esters, and 2-naphthylamine as
amine components and substituted benzaldehydes.
The reactions were performed in butanol in the pres-
ence of catalytic amounts of HCl on cooling to 5 C,
except the reactions with 2-naphthylamine derivatives,
which were performed with refluxing for 15 min.
The catalyst is required to activate the azomethine in
the reaction with relatively low-reactive antipyrine
whose amide carbonyl does not enolize and enter the
reaction yielding cyclic products. In the presence of
an acid catalyst, the antipyrine molecule as a typical
nucleophile adds to the azomethine bond to form a
new C C bond (presumed pathway 1 in the scheme
below).
All the synthesized antipyrine derivatives IIIa IIIc,
IIIf IIIh, IIIk IIIm, and IIIp IIIr, when heated in
the presence of HCl, decompose to p-aminobenzoic
acid or its esters (or to 2-naphthylamine), the corre-
sponding benzaldehyde, and arylmethylenediantipy-
rine IVc IVe (pathway 3).
In this cleavage, only a half of the benzaldehyde
fragments are released in the form of free benzalde-
hyde, and the remaining half of the fragments chemi-
cally bind two antipyrine molecules. Apparently, in
this case the compounds undergo complete hydrolytic
cleavage to the starting substances. In a strongly acid-
ic solution, the conditions for the reaction of p-amino-
benzoic acid, its esters, or 2-naphthylamine with benz-
aldehyde are unfavorable; therefore, these compounds
are always recovered in the free form. It is known [5]
that in a strongly acidic solution one benzaldehyde
molecule reacts with two antipyrine molecules to form
arylmethylenediantipyrine. Therefore, it becomes
understandable why free benzaldehyde is formed
among other products in the cleavage of the antipyrine
derivatives.
We found that the nucleophilic attack of the elec-
tron pair of antipyrine at the azomethine carbon atom
yields addition products only if the azomethine con-
tains electron-withdrawing substituents (IIa IIc, IIf
IIh, IIk IIm). In the reactions of antipyrine with azo-
methines IId, IIe, IIj, IIn, and IIo containing electron-
donor substituents, alkyl 4-{[(1,5-dimethyl-3-oxo-2-
phenyl-2,3-dihydro-1H-pyrazol-4-yl)(4-alkylphenyl)-
methyl]amino}benzoates are not formed under these
conditions, even on standing for more than 96 h.
Heating of the reaction mixture for 25 min caused for-
(R-Phenyl)(naphthyl-2-amino)methyl-1,5-dimethyl-
302

REACTION OF ANTIPYRINE WITH SCHIFF BASES
R
303
N
O
N
H
R
N
CH
1
+
N
O
NH
N
R
R
I
IIa IIt
IIIa IIIc, IIIf IIIh, IIIk IIIm, IIIp IIIr
IId, IIe, IIi, IIj, IIn, IIo, IIs, IIt
2
R
O
3
+ I
R
NH2
R
N
N
N
N
N
N
O
O
O
OH
R
IVa IVe
R = COOH, R = H (IIa, IIIa), Br (IIb, IIIb), NO2 (IIc, IIIc), OH (IId), OCH3 (IIe); R = CH3OCO, R = H (IIf, IIIf),
Br (IIg, IIIg), NO2 (IIh, IIIh), OH (IIi), OCH3 (IIj); R = C2H5OCO, R = H (IIk, IIIk), Br (IIl, IIIl), NO2 (IIm, IIIm),
OH (IIn), OCH3 (IIo); RC6H4 = 2-naphthyl-, R = H (IIp, IIIp), Br (IIq, IIIq), NO2 (IIr, IIIr), OH (IIs), OCH3 (IIt);
R = OH (IVa), OCH3 (IVb), H (IVc), Br (IVd), NO2 (IVe).
2-phenyl-1,2-dihydropyrazol-3-ones IIIp IIIr appear
to be more resistant to the hydramine cleavage.
Heating of Schiff bases IIp IIr with antipyrine in the
presence of concentrated HCl on a boiling water bath
for 15 min results in formation of naphthyldihydro-
pyrazolones IIIp IIIr, and only on refluxing of this
reaction mixture for 30 min the products are cleaved
into 2-naphthylamine, arylmethylenediantipyrine IVc
IVe, and the corresponding benzaldehyde. Arylidene-
naphthylamines IIs and IIt containing electron-donor
substituents do not form naphthyldihydropyrazolones;
heating of the reaction mixture results in direct forma-
tion and precipitation of arylmethylenediantipyrines
IVa and IVb.
these conditions can be prepared by a direct reaction
of an aromatic aldehyde and antipyrine in a 1 : 2 ratio,
as noted in [6].
The yields, melting points, and elemental analyses
of alkyl 4-{[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihy-
dro-1H-pyrazol-4-yl)(4-alkylphenyl)methyl]amino}-
benzoates IIIa IIIc, IIIf IIIh, and IIIk IIIm, (R-
phenyl)(naphthyl-2-amino)methyl-1,5-dimethyl-2-
phenyl-1,2-dihydropyrazol-3-ones IIIp IIIr, and
4-{[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-yl)(4-alkylphenyl)methyl]-1,5-dimethyl-2-
phenyl-1,2-dihydro-3H-pyrazol-3-ones IVa IVe are
listed in Table 1.
The structures of IIIa IIIc, IIIf IIIh, IIIk IIIm,
1
Arylmethylenediantipyrines IVa IVe isolated under
IIIp IIIr, and IVa IVe were proved by H NMR and
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304
KOZLOV, BASALAEVA
Table 1. Yields, melting points, and elemental analyses of the synthesized alkyl 4-{[(1,5-dimethyl-3-oxo-2-phenyl-2,3-
dihydro-1H-pyrazol-4-yl)(4-alkylphenyl)methyl]amino}benzoates IIIa IIIc, IIIf IIIh, and IIIk IIIm, (R-phenyl)(naph-
thyl-2-amino)methyl-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-ones IIIp IIIr, and 4-{[(1,5-dimethyl-3-oxo-2-phenyl-
2,3-dihydro-1H-pyrazol-4-yl)(4-alkylphenyl)methyl]-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-ones IVa IVe
Found, %
Calculated, %
Comp.
no.
Yield,
%
mp,
C
Formula
C
H
N (Hlg)
10.22
C
H
N (Hlg)
IIIa
IIIb
IIIc
IIIf
IIIg
IIIf
IIIk
IIIl
IIIm
IIIp
IIIq
IIIr
IVa
IVb
IVc
IVd
IVe
40
43
35
50
55
51
60
55
43
54
65
57
75
47
60
51
43
160
72.60
61.00
65.43
73.00
61.70
66.03
73.50
62.30
66.64
80.10
67.40
72.37
72.45
72.94
74.86
64.00
68.27
5.58
C25H23N3O3
C25H22BrN3O3
C25H22N4O5
C26H25N3O3
C26H24BrN3O3
C26H24N4O5
C27H27N3O3
C27H26BrN3O3
C27H26N4O5
C28H25N3O
C28H24BrN3O
C28H24N4O3
C29H28N4O3
C30H30N4O3
C29H29N4O2
C29H27BrN4O2
C29H28N5O4
72.62
60.99
65.49
73.05
61.67
66.09
73.45
62.31
66.66
80.16
67.47
72.40
72.48
72.85
74.84
64.09
68.23
5.61
4.50
4.84
5.89
4.78
5.12
6.12
5.04
5.39
6.01
4.85
5.21
5.87
6.11
6.24
10.20
8.53 (16.23)
12.20
9.83
8.30 (15.78)
11.90
9.52
8.07 (15.35)
11.50
10.02
8.48 (16.03)
12.06
178 179
190
4.48
4.87
5.91
4.76
5.14
6.19
5.00
5.42
6.03
4.90
5.18
5.90
6.15
6.21
8.50 (16.25)
12.25
176a
9.85
175a
8.25 (15.75)
11.89
180
200 201a
164 165a
178
9.50
8.10 (15.37)
11.54
268b
9.97
240 241
285 286
152c
8.51 (16.00)
12.11
11.70
11.28
12.06
11.66
11.33
12.04
173
162
169c
5.03 10.33 (14.61)
5.51
5.01 10.31 (14.70)
5.49 13.73
178
13.76
a
b
c
Note: The melting points agree with the published data:
[7],
[8], and
[9].
IR spectroscopy and by mass spectrometry. The IR
spectra of these compounds contain bands at 1755
1600 (amide I) and 1540 1510 cm (amide II) cor-
A singlet at 2.80 3.42 ppm belongs to three protons
of the methyl group at the N atom. A doublet at 5.23
5.50 ppm with a coupling constant of 8 Hz corre-
sponds to the proton at the asymmetric C atom in
IIIa IIIc, IIIf IIIh, IIIk IIIm, and IIIp IIIr, and a
doublet at 6.64 6.95 ppm, to the NH proton. Two
doublets (2H each) at 6.53 6.76 and 7.04 7.90 ppm
are characteristic of the p-disubstituted benzene ring
in benzoates IIIb, IIIc, IIIg, IIIh, IIIl, and IIIm,
naphthyldihydropyrazolones IIIq and IIIr, and aryl-
methylenediantipyrines IVa, IVb, IVd, and IVe. A
singlet in the spectra of IIIf IIIh at 3.58 3.63 ppm
belongs to three protons of the COOCH3 group. A
quartet at 4.08 4.15 ppm (CH2) and a triplet at 1.40
1.53 ppm (CH3), observed in the spectra of IIIk IIIm,
belong to protons of the ethoxy group. A distinctive
feature of the 1H NMR spectra of IVa IVe is a singlet
at 5.08 5.18 ppm belonging to the proton at the
asymmetric carbon atom.
1
responding to the carbonyl group of antipyrine, and
1
also a band at 3410 3350 cm corresponding to the
secondary amino group of alkyl pyrazolylmethylami-
nobenzoates IIIa IIIc, IIIf IIIh, IIIk IIIm, and
IIIp IIIr. Compounds IIIb, IIIg, IIIl, IIIp, and IVd
1
exhibit a strong absorption band at 585 565 cm
assignable to the C Br stretching vibrations, and
compounds IIIc, IIIh, IIIm, IIIr, and IVe, pronounced
1
bands at 1370 1355 and 1545 1530 cm originating,
respectively, from the symmetric and antisymmetric
vibrations of N O bonds. Compound IVa exhibits a
1
band at 3550 3400 cm belonging to hydroxyl
stretching vibrations, and compound IVb, a charac-
teristic band of OCH3 stretching vibrations at
1
2845 cm . Alkyl benzoates IIIf IIIh and IIIk IIIm
1
exhibit a strong absorption band at 1600 1540 cm
assignable to the antisymmetric stretching vibrations
of the carboxylate ion CH3CO2 or C2H5CO2.
The mass spectra of IIIa IIIc, IIIf IIIh, IIIk
IIIm, IIIp IIIr, and IVa IVe show that the com-
pounds are unstable to electron impact. The molecular
peak (M+) is absent, and only fragment peaks are
detected. The strongest (100%) peak, m/z 188, belongs
to the antipyrine ion.
1
The H NMR spectra of IIIa IIIc, IIIf IIIh, IIIk
IIIm, IIIp IIIr, and IVa IVe (Table 2) contain a sin-
glet at 1.85 2.40 ppm corresponding to three methyl
protons at the double bond in the antipyrine moiety.
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REACTION OF ANTIPYRINE WITH SCHIFF BASES
305
Table 2. 1H NMR spectra of the synthesized alkyl 4-{[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)(4-
alkylphenyl)methyl]amino}benzoates IIIa IIIc, IIIf IIIh, and IIIk IIIm, (R-phenyl)(naphthyl-2-amino)methyl-1,5-di-
methyl-2-phenyl-1,2-dihydropyrazol-3-ones IIIp IIIr, and 4-{[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-
4-yl)(4-alkylphenyl)methyl]-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-ones IVa IVe, , ppm (J, Hz)
Comp.
no.
CH3,
s
N CH3,
s
NH, d
CH
Aromatic protons and protons of R and R
(3J 8.0)
IIIa
IIIb
IIIc
IIIf
IIIg
IIIh
IIIk
1.90
2.20
1.95
1.85
2.00
2.07
1.97
2.80
3.00
3.00
2.90
3.05
3.10
3.00
5.30 d
5.50 d
5.45 d
5.40 d
5.30 d
5.38 d
5.37 d
6.70
6.85
6.80
6.95
6.70
6.95
6.64
6.30 6.50 m, 7.28 7.43 m, 7.90 8.00 m, 11.00 br.s (1H, COOH)
6.55 d (9.2), 7.22 7.40 m, 7.67 d (9.8), 11.50 br.s (1H, COOH)
6.67 d (9.0), 7.30 7.54 m, 7.72 d (8.4), 10.90 br.s (1H, COOH)
3.63 s (3H, OCH3), 6.10 6.38 m, 7.18 7.45 m, 7.87 8.10 m
3.60 s (3H, OCH3), 6.53 d (8.9), 7.10 7.30 m, 7.60 d (8.0)
3.58 s (3H, OCH3), 6.62 d (9.2), 7.00 7.30 m, 7.68 d (8.9)
1.48 t (3H, OCH2CH3), 4.15 q (2H,OCH2CH3), 6.08 6.40 m, 7.20
7.50 m, 7.80 8.00 m
IIIl
2.03
2.00
2.87
2.95
5.45 d
5.40 d
6.78
6.83
1.40 t (3H, OCH2CH3), 4.10 q (2H, OCH2CH3), 6.72 d (8.6), 7.00
7.20 m, 7.74 d (8.0)
1.53 t (3H, OCH2CH3), 4.08 q (2H, OCH2CH3), 6.76 d (8.1), 6.90
7.10 m, 7.90 d (8.7)
IIIm
IIIp
IIIq
IIIr
IVa
IVb
IVc
IVd
IVe
2.25
2.18
2.21
2.38
2.36
2.40
2.39
2.36
3.17
3.13
3.21
3.31
3.38
3.37
3.42
3.20
5.23 d
5.26
6.90
6.87
6.85
7.35 8.03 m, 8.21 8.40 m, 8.80 8.93 m
6.62 d (9.9), 7.27 7.80 m, 7.90 d (10.0), 8.19 8.30 m, 8.90 8.95 m
6.70 d (9.6), 7.33 7.72 m, 7.85 d (8.7), 8.17 8.23 m, 8.70 8.87 m
6.72 d (9.7), 7.04 d (10.2), 7.38 7.52 m, 10.90 br.s (1H, OH)
3.73 s (3H, OCH3), 6.80 d (9.2), 7.12 d (9.0), 7.29 7.45 m
6.30 6.45 m, 6.50 6.72 m, 7.00 7.16 m
5.21 d
5.13 s
5.18 s
5.11 s
5.12 s
5.08 s
6.77 d (9.7), 7.08 d (9.9), 7.34 7.52 m
6.60 d (9.7), 7.15 d (9.3), 7.30 7.53 m
EXPERIMENTAL
IIm and antipyrine I (0.001 mol each) were dissolved
separately in 10 ml of alcohol on heating. The solu-
The IR spectra were recorded on a Nicolet Protégé-
tions were mixed, and three drops of concentrated
HCl were added. The mixture was stirred and left in a
refrigerator until crystals formed (10 to 48 h). Then
excess solvent was filtered off, and the residue was
treated with aqueous ammonia. The substances were
recrystallized from alcohol benzene, 2 : 1.
1
460 IR Fourier spectrometer. The H and 13C NMR
spectra were measured on Tesla BS-567A (100 MHz)
and Bruker AC-500 (500 MHz) spectrometers. Sam-
ples were prepared as 2 5% solutions in DMSO-d6;
the chemical shifts were determined relative to inter-
nal TMS. The mass spectra were taken on a Finnigan
MAT-Incos-50 spectrometer (ionizing electron energy
70 eV) and on a Hewlett Packard HP-890/5972 gas
chromatograph mass spectrometer (electron impact,
70 eV; HP-5MS 30000 0.25-mm column; station-
ary phase 5% PLMe Silicone, film thickness 0.25 m;
vaporizer temperature 250 C).
(R-Phenyl)(naphthyl-2-amino)methyl-1,5-di-
methyl-2-phenyl-1,2-dihydropyrazol-3-ones IIIp
IIIr. To a solution of 0.001 mol of arylmethylene-
naphthylamine IIp IIr in 15 ml of alcohol, we added
0.001 mol of antipyrine I and three drops of concen-
trated HCl. The mixture was heated on a boiling water
bath for 15 min. After cooling, the precipitated crys-
tals were filtered off, treated with aqueous ammonia,
and recrystallized from alcohol toluene, 2 : 1.
Arylmethyleneanilines IIa IIo and arylme-
thylene-2-naphthylamines IIp IIt were prepared by
the reactions of appropriate p-aminobenzoic acid
derivatives or 2-naphthylamine with alkylbenzalde-
hydes in an alcoholic solution as described in [10].
4-{[(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-
1H-pyrazol-4-yl)(4-alkylphenyl)methyl]-1,5-di-
methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-ones
IVa IVe. Arylmethyleneaniline IId, IIe, IIi, IIj, IIn,
or IIo, or aryl- methylenenaphthylamine IIs or IIt and
antipyrine I (0.001 mol each) were dissolved separately
in 10 ml of butanol on heating. The solutions were
Alkyl 4-{[(1,5-dimethyl-3-oxo-2-phenyl-2,3-di-
hydro-1H-pyrazol-4-yl)(4-alkylphenyl)methyl]-
amino}benzoates IIIa IIIc, IIIf IIIh, and IIIk
IIIm. Arylmethyleneaniline IIa IIc, IIf IIh, or IIk
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 2 2006

306
KOZLOV, BASALAEVA
mixed, and three drops of concentrated HCl were
added. The mixture was refluxed until crystals started
to precipitate (20 30 min); the precipitate that formed
after cooling was filtered off, treated with aqueous
ammonia, and recrystallized from ethanol.
4. Kozlov, N.S. and Isaeva, R.K., Tr. Perm. Sel’skokhoz.
Inst., 1965, vol. 29, coll. 2, p. 37.
5. Kozlov, N.S. and Nikolaev, A.D., Dokl. Akad. Nauk
SSSR, 1964, vol. 154, no. 6, p. 1382.
6. Stolz, F., Ber., 1896, vol. 29, p. 1826.
7. Kozlov, N.S. and Nikolaev, A.D., Tr. Perm. Sel’sko-
khoz. Inst., 1964, vol. 24, p. 3.
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