Synthesis and tuberculocidic activity of some 4-arylaminomethylene-3- methyl-1-(pyrimidin-2-yl)pyrazol-5(4H)-ones

Article abstract of DOI:10.1134/S1070363212010252

4-Arylaminomethylene-3-methyl-1-(6-methyl-4-oxo-1,4-dihydropyrimidin-2-yl) pyrazol-5(4H)-ones were synthesized by a three-component reaction between the 6-methyl-2-(3-methyl-5-oxo-2,5-dihydropyrazol-1-yl)pyrimidin-4(1H)-one, triethoxymethane, and an aroma

Full text of DOI:10.1134/S1070363212010252

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 1, pp. 153–156. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © A.V. Erkin, V.I. Krutikov, A.A. Ivanov, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 1, pp. 156–159.
Synthesis and Tuberculocidic Activity
of Some 4-Arylaminomethylene-3-methyl-
1-(pyrimidin-2-yl)pyrazol-5(4H)-ones
A. V. Erkin, V. I. Krutikov, and A. A. Ivanov
St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: kruerk@yandex.ru
Received April 26, 2011
Abstract—4-Arylaminomethylene-3-methyl-1-(6-methyl-4-oxo-1,4-dihydropyrimidin-2-yl)pyrazol-5(4H)-
ones were synthesized by a three-component reaction between the 6-methyl-2-(3-methyl-5-oxo-2,5-
dihydropyrazol-1-yl)pyrimidin-4(1H)-one, triethoxymethane, and an aromatic amine. These compounds were
found to exist as aminomethyleneketones regardless of the electronic effects of substituents in the aromatic
fragments. The resulting compounds showed pronounced tuberculocidic activity.
DOI: 10.1134/S1070363212010252
Ar
The detected ability of some 4-arylidene-3-methyl-
1-(6-methyl-4-oxo-1,4-dihydropyrimidin-2-yl)pyrazol-
5(4H)-ones (I) to inhibit the Mycobacterium
tuberculosis cell growth [1] stimulates a search for the
substances with similar effects among the structurally
similar compounds. The modification of arylidene-
pyrazolones I through fusing pyrimidine and cyclo-
pentane rings led to the loss of tuberculocidic
properties in the obtained 4-arylidene-3-methyl-1-(4-
oxo-3,4-dihydrocyclopenta[d]pyrimidin-2-yl)-pyrazol-
5(4H)-ones [2]. The extension of the series of com-
pounds I by varying the substituents in the aromatic
ring was found to be hindered because the condensation
of the initial ethyl acetoacetate (6-methyl-4-oxo-3,4-
dihydropyrimidin-2-yl)ethyl hydrazone [3] or 6-methyl-
2-(3-methyl-5-oxo-2,5-dihydropyrazol-1-yl) pyrimidin-
4(1H)-one III [4] with aromatic aldehydes leds to the
products of the desired structure only with the reagents
containing an auxochromic substituent in the para-
position of the ring. The arylidenepyrazolone analogs
of I with the minimally transformed structure are 4-
arylaminomethylene-3-methyl-1-(6-methyl-4-oxo-1,4-
dihydropyrimidin-2-yl)pyrazol-5(4H)-ones (IVa–IVk).
In order to study their tuberculocidic action we have
synthesised these compounds by a three-component
reaction between the pyrazolone (III), triethoxy-
methane, and aromatic amines.
Me
NH
N
H
Me
N
O
O
(EtO)3CH + ArNH2
N
N
HN
N
HN
N
Me
O
Me
O
III
IVа_IVk
solvent till the solidification of the reaction mixture.
When the mixture did not solidify despite an increase
in the time of contact of the initial compounds, the
formed thick oil was treated with benzene to cause the
product crystallization. To purify arylaminomethylene-
pyrazolones IVa–IVk obtained they were crystallized
once or twice from a suitable solvent or solvent
mixture, to reach chromatographic purity of the target
compound (Table 1).
Structure of arylaminomethylenepyrazolones IV is
confirmed by the data of the H NMR spectra, which
1
contain multiplets of aromatic protons in the region of
7.2–7.9 ppm, as well as the characteristic doublets of
protons of exocyclic CH groups near 8.5 ppm and NH
about 11.0 ppm. In some cases the signals of
secondary exocyclic amino groups appear as an
unresolved singlet. Table 2 lists more detailed spectral
parameters of compounds IVa–IVk.
The reaction was performed by heating the
equimolar mixture of reagents at 70–80°C without a
153

154
ERKIN et al.
Table 1. Yields, melting points, TLC,and elemental analyses of 4-arylaminomethylene-3-methyl-1-(6-methyl-4-oxo-1,4-
dihydropyrimidin-2-yl)pyrazol-5(4H)-ones IVa–IVk
Found, %
Calculated, %
Comp.
no.
Yield,a
%
mp,
°С
Ar
Rf
Formula
C
H
N
C
H
N
Ph
50
54
63
15
23
42
38
15
24
41
37
277
263
240
211
275
258
262
260
291
248
227
0.43
0.42
0.42
0.42
0.43
0.43
0.43
0.44
0.44
0.44
0.43
61.82
4.56
22.51
С16H15N5O2
62.13
4.89
22.64
IVа
IVb
IVc
IVd
IVe
IVf
IVg
IVh
IVi
4-MeC6H4
4-EtC6H4
62.75
63.88
64.76
58.53
55.61
49.57
44.05
50.51
50.42
54.61
5.05
5.56
5.89
4.30
4.23
3.54
3.34
3.05
4.08
4.27
21.46
20.62
19.82
21.07
20.13
17.78
15.78
18.34
17.13
18.67
C17H17N5O2
63.15
64.08
64.94
58.71
55.90
49.50
44.16
50.81
50.76
54.63
5.30
5.68
6.02
4.31
4.10
3.63
3.24
3.46
4.01
4.31
21.66
20.76
19.93
21.40
20.37
18.04
16.09
18.52
17.41
18.74
C18H19N5O2
4-i-PrC6H4
4-FC6H4
C19H21N5O2
C16H14FN5O2
C16H14ClN5O2
C16H14BrN5O2
C16H14IN5O2
C16H13Cl2N5O2
C17H16BrN5O2
C17H16ClN5O3
4-ClC6H4
4-BrC6H4
4-IC6H4
3,4-Cl2C6H3
3-Me-4-BrC6H3
3-Cl-4-MeOC6H3
IVj
IVk
a After purification by recrystallization.
The arylaminomethylenepyrazolones IV exist
preferably as β-amino-α,β-unsaturated ketones, as seen
from their IR spectra, and virtually the same is correct
for the whole series despite the difference in the
directions of the inductive effects of substituents in the
para-position of the aromatic ring. Thus, the frequency
of the stretching vibrations of C=O and C=C bonds,
which are in conjugation, are 1682 and 1558, 1685 and
1564 cm–1 for compounds IVb, IVe, respectively,
indicating the dominant influence of the resonance
effect of the halogen atom in the molecule of
fluorophenylaminomethylenepyrazolone IVe. At the
same time, a significant decrease in the frequency of
stretching vibrations (Δν 100 cm–1) of the exocyclic
NH bond of compound IVd compared with that of the
methylphenylaminomethylenepyrazolone IVb (νNH
3512 cm–1) indicates its weakening caused by the
inductive effects of substituents, and shows some
disturbance of total conjugation in this structure
resulting from it. Such a conclusion follows from the
analysis of UV spectra of compounds IVb, IVe, which
contain an absorption band corresponding to the π→π*
transitions in the conjugation chains involving the aryl
fragments, therewith for the peaks a blue shift is observed
(Δλ = 11 nm) in the case of fluorophenylamino-
methylenepyrazolone IVe and a red shift (Δλ = 10 nm),
in the case of methylphenylaminomethylenepyra-
zolone IVb relative to the maximum (λmax 344 nm) of
the absorption bands of unsubstituted arylamino-
methylenepyrazolone IVa (see the figure). However, a
significant (Δε ~ 1000 l mol–1 cm–1) increase in the
molar absorption coefficient of compound IVe com-
pared to the same characteristic absorption bands of
compounds IVb provides additional evidence that the
former is not involved in tautomeric rearrangement,
which would lead to a significant change in its structure.
The biological screening of arylaminomethylene-
pyrazolones IVa–IVk in vitro showed a marked
inhibitory effect of the some compounds on the cells of
Mycobacterium tuberculosis strain H37Rv. Com-
pounds IVa, IVb, IVe, IVf, and IVh show 100%
inhibition of reproduction of a biological object at a
concentration IC100 = 0.0125 g l–1, compound IVg, at
IC100 = 0.05 g l–1. The IC100 values indicate a low
sensitivity of this strain to the nature of the substituent
in para position of the ring. The arylaminomethylene-
pyrazolones IVi–IVk containing
a
disubstituted
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 1 2012

SYNTHESIS AND TUBERCULOCIDIC ACTIVITY
155
1
Table 2. H NMR spectra of 4-arylaminomethylene-3-methyl-1-(6-methyl-4-oxo-1,4-dihydropyrimidin-2-yl) pyrazol-5(4H)-
ones IV
δ,а ppm
Comp.
no.
Me
Me
CH
Ar
–CH=
NHe
NH
others groups
2.24 s (Me)
2.19 s
2.30 s
5.92 s
7.24–7.62 m
8.59 d
11.10 d
11.92
IVа
IVb
IVc
2.18 s
2.19 s
2.32 s
2.28 s
5.92 s 7.22, 7.24 d; 7.48, 7.50 d
5.91 s 7.24, 7.26 d; 7.50, 7.52 d
8.55 d
8.56 d
11.08 d
11.09 d
11.96
11.98 1.20 t (СH3CH2), 2.62 q
(СH3CH2)c
2.19 s
2.29 s
5.92 s 7.27, 7.29 d; 7.50, 7.52 d 8.54, 8.57 d
11.10, 11.13 d 11.96 1.22 s (Me), 1.23 s (Me),
IVd
2.91 m (СH)c
b
2.21 s
2.21 s
2.19 s
2.20 s
2.19 s
2.20 s
2.17 s
2.34 s
2.31 s
2.29 s
2.29 s
2.30 s
2.30 s
2.27 s
5.90 s
5.90 s 7.42, 7.44 d; 7.65, 7.66 d 8.55, 8.58 d
5.95 s 7.61 s 8.54, 8.57 d
5.89 s 7.44, 7.46 d; 7.72, 7.74 d 8.55, 8.58 d
7.19–7.66 m
8.51, 8.54 d
11.14 br.s
11.14 br.s
–
IVe
IVf
IVg
IVh
IVi
b
–
11.09, 11.13 d 11.90
11.06, 11.09 d 11.85
b
5.98 s
5.89 s
5.94 s
7.67–8.06 m
7.37–7.60 m
7.16–7.85 m
8.54, 8.57 d
8.56, 8.58 d
11.08 br.s
11.06 br.s
–
b
–
2.40 s (Mе)
IVj
IVk
8.47, 8.50 d
11.03, 11.06 d 11.96
3.87 s (MеО)
a
b
c
Integral intensity of the signals corresponds to the number of proton groups. Do not appear due to deuterium exchange. The signal
center.
aromatic fragment were unable to inhibit the growth of
the mycobacterial cells even at increasing the IC100
values to 0.1 g l–1. The results obtained suggest that the
structural transformation of arylidene pyrazolones I at
the introduction of exocyclic amino group leads to an
increased level of their tuberculocidic activity.
6-Methyl-2-(3-methyl-5-oxo-2,5-dihydropyrazol-1-
yl)pyrimidin-4(1H)-one III was prepared according to
[5].
4-Arylaminomethylene-3-methyl-1-(6-methyl-4-
oxo-1,4-dihydropyrimidin-2-yl)pyrazol-5(4H)-ones
EXPERIMENTAL
ε, l mol–1 сm–1
1
The H NMR spectra were recorded on a Bruker
WM-400 spectrometer (operating frequency 400.13
MHz) in DMSO-d6, as internal reference were used the
signals of the residual protons of the solvent. The IR
spectra were recorded on an FSM-1201 IR-Fourier
spectrometer in KBr tablets. The UV spectra were
recorded on an SF-26 spectrophotometer, solvent
DMF, the concentration of a substance 0.3×10–4 M.
The individuality of compounds was monitored by
TLC on Silufol UV-254 plates in the system of 2-
propanol–25% aqueous ammonia, 3:1, development of
the spots was performed under UV light. Elemental
analyses were carried out on a Hewlett Packard B-185
CHN-analyzer.
λ, nm
UV spectra: (1) compound IVe, (2) IVa, and (3) IVb.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 1 2012

156
ERKIN et al.
(IV). A mixture of 0.0015 mol of pyrimidylpyrazolone
III, 0.0015 mol of triethoxymethane, and 0.0015 mol
of an aromatic amine was heated at 70–80°C until
solidification. After cooling, the reaction product was
ground and recrystallized. The oily products were
triturated with 10 ml of benzene, the precipitates
formed were filtered off and purified by recrystalliza-
tion. Compounds IVa–IVc were recrystallized from
ethanol–water, 8:2, IVd, from ethanol–water mixture,
1:1, IVe, from acetic acid–water mixture, 4:6, IVf,
from acetic acid–water mixture, 7:3, IVg, IVj, from
DMF, IVh, IVk, from acetic acid–water, 1:1, IVi,
from acetic acid. Purified products were washed with
ethanol and dried at 80°C.
Pavlov State Medical University) for performing the
microbiological research, and to I.V. Klaptyuk
(Scientific Research Institute of the Fire Defence,
Ministry of Emergency Situations of Russia) for
recording the IR spectra.
REFERENCES
1. Erkin, A.V. and Krutikov, V.I., Abstract of Papers, 10th
Int. Scientific-Research Conf. “Science-Capacious
Chemical Technologies,” Volgograd, 2004, vol. 1, p. 245.
2. Erkin, A.V. and Krutikov, V.I., Zh. Obshch. Khim.,
2008, vol. 78, no. 2, p. 324.
3. Erkin, A.V., Krutikov, V.I., and Chubraev, M.A., Zh.
Obshch. Khim., 2004, vol. 74, no. 3, p. 466.
4. Cristea, I., Studia Universitatis Babes-Bolyai, Seria
Chemia, 1988, vol. 33, no. 2, p. 61.
ACKNOWLEDGMENTS
The authors express their deep gratitude to
Proffessor Tets V.V. and his colleagues (St. Petersburg
5. Erkin, A.V. and Krutikov, V.I., Zh. Obshch. Khim.,
2009, vol. 79, no. 7, p. 1168.
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