1-(Pyrimidin-4-yl)pyrazol-5(4H)-one derivatives: I. Synthesis of 3-methyl-1-(6-methyl-2-methylsulfanylpyrimidin-4-yl)-pyrazol-5-ol and specificity of its Knoevenagel reaction

Article abstract of DOI:10.1134/S1070363211020186

3-Methyl-1-(6-methyl-2-methylsulfanylpyrimidin-4-yl)-1H-pyrazol-5-ol available via cyclocondensation of 6-methyl-2-methylsulfanylpyrimidin-4- ylhydrazine with ethyl acetoacetate reacted with aromatic aldehydes to give two kinds of products, 4-arylmethylid

Full text of DOI:10.1134/S1070363211020186

ISSN 1070-3632, Russian Journal of General Chemistry, 2011, Vol. 81, No. 2, pp. 392–396. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © A.V. Erkin, V.I. Krutikov, 2011, published in Zhurnal Obshchei Khimii, 2011, Vol. 81, No. 2, pp. 294–298.
1-(Pyrimidin-4-yl)pyrazol-5(4H)-one Derivatives: I. Synthesis
of 3-Methyl-1-(6-methyl-2-methylsulfanylpyrimidin-4-yl)-
pyrazol-5-ol and Specificity of Its Knoevenagel Reaction
A. V. Erkin and V. I. Krutikov
St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: kruerk@yandex.ru
Received May 25, 2010
Abstract—3-Methyl-1-(6-methyl-2-methylsulfanylpyrimidin-4-yl)-1H-pyrazol-5-ol available via cyclocondensation
of 6-methyl-2-methylsulfanylpyrimidin-4-ylhydrazine with ethyl acetoacetate reacted with aromatic aldehydes
to give two kinds of products, 4-arylmethylidene-5-oxo-4,5-dihydropyrazole and arylbis(5-hydroxypyrazol-4-
yl)methane derivatives , depending on the substituent in the aromatic aldehyde.
DOI: 10.1134/S1070363211020186
1-Aryl-1H-pyrazol-5(4H)-ones products of their
condensation with aromatic aldehydes have been
extensively studied [1], whereas structurally related 1-
pyrimidinyl-1H-pyrazol-5(4H)-ones and their 4-
arylmethylidene derivatives have been studied only in
part. Transformations of 1-(pyrimidin-2-yl)-1H-pyrazol-
5(4H)-ones in the Knoevenagel condensation have
been reported [2–5], while there are no analogous data
for isomeric 1-(pyrimidin-4-yl)-1H-pyrazol-5(4H)-ones I.
intermediate ethyl 3-[2-(6-methyl-2-methylsulfanyl-
pyrimidin-4-yl)hydrazono]butanoate (IV) (Scheme 1).
Chromatographically pure hydrazone IV may be isolated
as crystalline substance by reaction of hydrazine III
with ethyl acetoacetate in butan-1-ol with simultaneous
removal of liberated water as azeotrope. However, to
avoid the loss of an appreciable amount of compound
IV, its further purification is unreasonable, despite
considerable difference in the melting points of the
crude product and analytical sample.
The goal of the present work was to synthesize one
of pyrimidinylpyrazolones I, 3-methyl-1-(6-methyl-2-
methylsulfanylpyrimidin-4-yl)-1H-pyrazol-5-ol (II),
and to determine the structure of products of its
reaction with aromatic aldehydes having typical
electron-donating and electron-withdrawing substituents.
Compound II was synthesized by conventional cyclo-
condensation of 6-methyl-2-methylsulfanylpyrimidin-
4-ylhydrazine (III) with ethyl acetoacetate through
Treatment of hydrazone IV with potassium
hydroxide in aqueous ethanol at 50°C gave potassium
salt of compound II, and neutralization of an aqueous
solution of that salt with acetic acid afforded target
pyrazole II. To improve the yield of II, the cyclization
of hydrazone IV should be carried out at a temperature
not exceeding 50°C; otherwise, the reaction is accom-
panied by considerable tarring.
Scheme 1.
Me
N
HN
COOEt
N
HO
N
N
NHNH2
NH Me
N
KOH
N
AcCH2COOEt
N
MeS
Me
MeS
N
Me
MeS
N
Me
III
IV
II
392

1-(PYRIMIDIN-4-YL)PYRAZOL-5(4H)-ONE DERIVATIVES: I.
393
Hydrazine III used as starting compound in the
synthesis of pyrazole II was prepared in turn by
reaction of 4-chloro-6-methyl-2-methylsulfanylpyri-
midine (V) with excess hydrazine hydrate in boiling
ethanol [6]. Hydrazinolysis of chloropyrimidine V at
80–90°C under solvent-free conditions was not
successful. After cooling to 0–5°C, a product identical
to initial pyrimidine V (according to the TLC data)
separated from the reaction mixture.
resulted in the isolation of a small amount of an
unidentified hygroscopic substance with an Rf value of
0.89 (A); this substance was very poorly soluble in
methylene chloride, diethyl ether, and benzene, and it
melted in the temperature range from 120 to 140°C.
Scheme 2.
O
Cl
PCl5
HN
MeS
N
The presence in molecule V of a sulfide moiety,
which may also be replaced by the action of hydrazine
hydrate, creates some difficulties in the purification of
hydrazine III from the potential exhaustive hydra-
zinolysis product, 2,4-dihydrazino-6-methylpyrimidine
[6]. Taking into account formation of trace amount of
methanethiol during the synthesis of compound III and
N
Me
MeS
N
Me
VI
V
Pyrazole II reacted with aromatic aldehydes under
the Knoevenagel reaction conditions to give two kinds
of products whose structure was determined by the
substituent in the aldehyde component. The condensa-
tion of compound II with 4-dimethylamino-benzal-
dehyde in ethanol in the presence of diethylamine
afforded 4-(4-dimethylaminobenzyl-idene)-3-methyl-1-
(6-methyl-2-methylsulfanylpyrimidin-4-yl)-pyrazol-5-
(4H)-one (VII) (Scheme 3).
1
the absence in the H NMR spectrum of III of a split
signal assignable to 5-H, the contribution of exhaustive
hydrazinolysis may be regarded as insignificant.
According to published data, intermediate chloride
V is obtained by chlorination of 6-methyl-2-methyl-
sulfanylpyrimidin-4(3H)-one (VI) with phosphoryl
chloride [7] or a mixture of phosphoryl chloride with
phosphorus pentachloride [8]. However, we failed to
reproduce these procedures, and we synthesized
compound V by treatment of pyrimidinone VI with
phosphorus pentachloride in the temperature range
from 75 to 130°C (Scheme 2). The reaction mixture
was heated until hydrogen chloride no longer evolved,
and the product was isolated by extraction with
methylene chloride (after preliminary removal of
phosphoryl chloride and decomposition of its residual
amount with ice). Our attempt to reproduce the
procedure for chlorination of VI reported in [7]
1
The H NMR spectrum of pyrazolone VII contains
a characteristic [2, 9] singlet from proton in the
exocyclic –CH= group at δ 7.8 ppm, and a strong
absorption band is observed in its UV spectrum at
about λ 465 nm; the latter corresponds to π–π*-
electron transitions in the direct conjugation chain. The
reaction of pyrazole II with 4-nitrobenzaldehyde under
analogous conditions resulted in the formation of bis-
[5-hydroxy-3-methyl-1-(6-methyl-2-methylsulfanyl-
pyrimidin-4-yl)-1H-pyrazol-4-yl](4-nitrophenyl)methane
diethylammonium salt (VIII) even when equimolar
Scheme 3.
NO2
Me
Me
Me
N
Me
Me
N
R1CHO
R2CHO
N
N
O
S
N
II
HO
S
OH
N
N
N
N
N
Me
Me
Me
N
VII
Me
Me
Me
R1 = 4-Me2NC6H4, R2 = 4-O2NC6H4.
S
VIII
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 2 2011

394
ERKIN, KRUTIKOV
amounts of the reactants were used. Compound VIII
displayed in the 1H NMR spectrum a singlet at about δ
4.7 ppm from the exocyclic methine proton, which is
typical of aldehyde addition products to two pyrazol-
5(4H)-one molecules [10]. The intensity ratio of the
CH and aromatic protons was 1:6. By neutralization of
diethylammonium salt VIII with acetic acid we
isolated arylbispyrazolylmethane IX as free base.
Unlike diethylammonium salt VIII, the 1H NMR
spectrum of IX contained no signals from ethyl
protons at δ 1.1 and 2.9 ppm. In the UV spectrum of
bispyrazolylmethane IX we observed absorption bands
with their maxima at λ 255 (logε = 4.73) and 300 nm
(log ε = 4.40), whose positions are similar to those
typical of isolated chromophores of pyrazole II.
Considerable increase in the intensity of these bands as
compared to the spectrum of II is related to the
contribution of substituted benzene ring.
A mixture of benzylidenepyrazolone VII and
intermediate X (R′ = Me) can be separated by single
crystallization from appropriate solvent. The mixture
obtained by reaction of pyrazole II with 4-diethyl-
aminobenzaldehyde and consisting of α-hydroxyl-
benzylpyrazolone X (R′ = Et) [Rf 0.83 (B)] and 4-(4-
diethylaminobenzylidene)-3-methyl-1-(6-methyl-2-
methylsulfanylpyrimidin-4-yl)-1H-pyrazol-5(4H)-one
(XI) [a bright spot with Rf 0.63 (B) under visible light]
cannot be separated in such a way. Moreover, neither
heating of product mixture X (R′ = Et)/XI at 100°C
under reduced pressure over a potent dehydrating
agent, phosphoric anhydride, nor heating in benzene
in the presence of a catalytic amount of concentrated
sulfuric acid with simultaneous removal of water as
azeotrope was efficient. Although the presence of α-
hydroxybenzylpyrazolone X (R′ = Et) in the initial
mixture followed from the observed separation of
water in the Dean–Stark trap, its transformation into
pyrazolone XI was not complete.
The formation of benzylidenepyrazolone VII may
be interpreted on the basis of our previous assumption
[9] that such compounds are stabilized due to
participation of n electrons of the substituent in the
overall conjugation system (zwitterionic canonical
structure A). Taking into account the opposite
electronic effect of nitro group, such stabilization of
hypothetical 3-methyl-1-(6-methyl-2-methyl-sulfanyl-
pyrimidin-4-yl)-4-(4-nitrobenzylidene)-1H-pyrazol-5-
(4H)-one is hardly probable, and deficit of electron
density on the exocyclic carbon atom may be
compensated only by addition of the second pyrazole
II molecule with the formation of arylbispyrazolyl-
methane VIII. In some cases, the electron-donor effect
of p-dialkylamino-substituted benzene ring is so strong
that it hampers dehydration of intermediate 4-(α-
hydroxy-4-dialkylaminobenzyl)-3-methyl-1-(6-methyl-
2-methylsulfanylpyrimidin-4-yl)-1H-pyrazol-5(4H)-
ones X to compounds like VII.
R'
N R'
HO
Me
H
N
O
N
R
X
R = 6-Methyl-2-methylsulfanylpyrimidin-4-yl.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
WM-400 spectrometer at 400.13 MHz using CDCl3
and DMSO-d6 as solvents and references. The UV
spectra were measured on an SF-26 spectrophotometer
from solutions in ethanol with concentrations of
9.52×10–5 (compound II), 9.79×10–5 (VII), and
2.016×10–5 M (IX). The purity of the isolated
compounds was checked by thin-layer chromatography
on Silufol UV-254 plates using the following solvent
systems as eluents: acetone–hexane (2:1) (A), butan-1-
ol–acetic acid–water (1:1:1) (B), acetone–heptane
(1:1) (C), and acetone–hexane (1:1) (D); spots were
detected under UV light. The elemental compositions
were determined on a Leco CHNS-932 analyzer.
Me
Me
N
Me
N
O
N
R
Me
Me
Me
N+
−O
N
N
R
A
R = 6-Methyl-2-methylsulfanylpyrimidin-4-yl.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 2 2011

1-(PYRIMIDIN-4-YL)PYRAZOL-5(4H)-ONE DERIVATIVES: I.
395
6-Methyl-2-methylsulfanylpirimidin-4(3H)-one (VI)
was synthesized according to the procedure described
in [11].
(CDCl3), δ, ppm: 1.26 t (3H, CH2CH3), 1.96 s (3H,
Me), 2.34 s (3H, Me), 2.49 s (3H, Me), 3.34 s (2H,
CH2), 4.17 q (2H, OCH2), 6.67 s (1H, CH), 7.92 s (1H,
NH). Found, %: C 50.77; H 6.21; N 19.39.
C12H18N4O2S. Calculated, %: C 51.04; H 6.43; N
19.84.
3-Methyl-1-(6-methyl-2-methylsulfanylpyrimidin-
4-yl)pyrazol-5-ol (II). A solution of 1 g of hydrazine
III in 30 ml of anhydrous butan-1-ol was heated to
120°C, 0.76 g of ethyl acetoacetate was added, and the
mixture was heated for 1 h under reflux in a flask
equipped with a Dean–Stark trap. The mixture was
then evaporated under reduced pressure, the residue
was left to stand until it crystallized completely, the
crystalline material was ground with 15 ml of hexane,
and the precipitate was filtered off, washed with
hexane, and dried in air. We thus isolated 1.11 g (67%)
of hydrazone IV with mp 87°C, Rf 0.45 (C), which was
brought into further transformations without additional
purification. A solution of 0.26 g of potassium
hydroxide in 5 ml of water was added to a solution of
1.11 g of hydrazone IV in 15 ml of ethanol, the
mixture was heated for 1 h at 50°C and evaporated to
dryness under reduced pressure, the residue was
dissolved in 10 ml of water, the aqueous solution was
filtered and acidified with acetic acid, and the
precipitate was filtered off, washed with cold water,
dried over phosphorus pentaoxide under reduced
pressure, recrystallized from cyclohexane, and dried in
a high vacuum. Yield of pyrazole II 0.51 g (55%), mp
4-Chloro-6-methyl-2-methylsulfanylpyrimidine
(V). A mixture of 7.8 g of pyrimidinone VI and 10.4 g
of phosphorus pentachloride was heated to 75–80°C,
the temperature was then gradually raised to 125–130°C,
and the mixture was kept until hydrogen chloride no
longer evolved. Phosphoryl chloride was distilled off
under reduced pressure from the resulting thick
solution, the residue was cooled to 0–5°C, and finely
crushed ice and 30 ml of methylene chloride were
added. The organic phase was separated, the aqueous
phase was extracted with methylene chloride
(2×30 ml), the extracts were combined with the
organic phase, dried over anhydrous sodium sulfate
over a period of 24 h, and filtered, the solvent was
distilled off completely under atmospheric pressure,
and the residue was distilled under reduced pressure, a
fraction with bp 110–115°C (8–10 mm) being
collected. Yield 6.19 g (71%), mp 37°C, Rf 0.71 (D);
published data [7]: mp 38°C.
4-(4-Dimethylaminobenzylidene)-3-methyl-1-(6-
methyl-2-methylsulfanylpyrimidin-4-yl)-1H-pyrazol-
5(4H)-one (VII). Diethylamine, 0.15 g, was added to a
solution of 0.5 g of pyrazole II in 10 ml of ethanol, the
mixture was stirred for a short time, a solution of 0.32 g
of 4-dimethylaminobenzaldehyde in 5 ml of ethanol
was added, and the mixture was stirred for 1 h at room
temperature, heated for 2 h at 40–50°C, and left to
stand for 24 h. The resulting suspension was
evaporated to dryness under reduced pressure, the
residue was treated with 5 ml of cold ethanol under
stirring over a period of 2 h, and the precipitate was
filtered off. The product was recrystallized from
ethanol containing a small amount of dimethylform-
amide to ensure complete dissolution, washed with a
minimal amount of cold ethanol, and dried under
reduced pressure over phosphoric anhydride. Yield
1
123°C, Rf 0.79 (B). H NMR spectrum (CDCl3), δ,
ppm: 2.22 s (3H, Me), 2.46 s (3H, Me), 2.54 s (3H,
Me), 5.40 s (1H, CH), 7.26 s (1H, CH), 11.80 br.s (1H,
OH). UV spectrum, λmax, nm (log ε): 248 (4.42), 310
(4.07). Found, %: C 50.28; H 5.37; N 23.55.
C10H12N4OS. Calculated, %: C 50.83; H 5.12; N 23.71.
6-Methyl-2-methylsulfanylpyrimidin-4-ylhyd-
razine (III). A mixture of 4 g of 4-chloropyrimidine V
and 3.42 g of hydrazine hydrate in 30 ml of ethanol
was heated for 1 h under reflux, and the solvent was
distilled off under reduced pressure. The residue was
treated with 20 ml of benzene, and the undissolved
material was filtered off and dried in air. This
procedure was repeated with the use of water instead
of benzene. The dry product was recrystallized from
benzene and dried for 3 h at 70°C. Yield 1.93 g (48%),
mp 146°C, Rf 0.42 (B); published data [6]: mp 142–
143°C.
1
0.15 g (19%), mp 202°C, Rf 0.78 (B). H NMR
spectrum (CDCl3), δ, ppm: 2.36 s (3H, Me), 2.46 s
(3H, Me), 2.61 s (3H, Me), 3.15 s (6H, NMe), 6.72 d
(2H, Harom), 7.27 s (1H, CH), 7.80 s (1H, CH), 8.50 d
(2H, Harom). UV spectrum, λmax, nm (log ε): 250
(4.44), ~465 (4.4). Found, %: C 61.80; H 5.57; N
19.16. C19H21N5OS. Calculated, %: C 62.10; H 5.76; N
19.06.
Ethyl 3-[(6-methyl-2-methylsulfanylpyrimidin-4-
yl)hydrazono]butanoate (IV) was synthesized as
described above. An analytical sample was obtained by
recrystallization from heptane, followed by drying in a
high vacuum. mp 90°C, Rf 0.45 (C). 1H NMR spectrum
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 2 2011

396
ERKIN, KRUTIKOV
4,4′-(4-Nitrobenzylidene)bis[3-methyl-1-(6-methyl-
ACKNOWLEDGMENTS
2-methylsulfanylpyrimidin-4-yl)-1H-pyrazol-5-ol]
(IX). Diethylamine, 0.15 g, was added to a solution of
0.5 g of pyrazole II in 10 ml of ethanol, the mixture
was stirred for a short time, a solution of 0.32 g of 4-
nitrobenzaldehyde in 5 ml of ethanol was added, and
the mixture was stirred for 1 h at room temperature,
heated for 1 h at 40–50°C, and left to stand for 24 h.
The precipitate was filtered off, washed with a
minimal amount of cold ethanol, recrystallized from
acetonitrile containing a small amount of dimethyl-
formamide to ensure complete dissolution, and dried
under reduced pressure to obtain 0.27 g (18%) of
compound VIII as diethylammonium salt, mp 173°C,
The authors are grateful to Novbytkhim Corporation
(St. Petersburg, Russia) for comprehensive support of
the present study.
REFERENCES
1. Heterocyclic Compounds, Elderfield, R.C., Ed., New
York: Wiley, 1957, vol. 5.
2. Cristea, I., Stud. Univ. Babes-Bolyai, Chem., 1988, vol. 33,
no. 2, p. 61.
3. Cristea, I. and Panea, I., Stud. Univ. Babes-Bolyai,
Chem., 1995, vol. 40, nos. 1–2, p. 171.
1
4. Panea, I. and Cristea, I., Stud. Univ. Babes-Bolyai,
Chem., 1996, vol. 41, no. 1, p. 9.
Rf 0.91 (B). H NMR spectrum (DMSO-d6), δ, ppm:
1.16 s (6H, NCH2CH3), 2.17 s (6H, Me), 2.38 s (6H,
Me), 2.49 (SMe, obscured by the solvent), 2.92 d (4H,
NCH2), 4.69 s (1H, CH), 7.51 d (2H, Harom), 7.65 s
(2H, CH), 8.05 d (2H, Harom). Found, %: C 54.11; H
5.82; N 20.17. C27H27N9O4S2·C4H11N. Calculated, %:
C 54.80; H 5.60; N 20.62. Diethylammonium salt of
VIII, 0.27 g, was dissolved in 5 ml of acetic acid, and
15 ml of water was gradually added under stirring to
the solution. The precipitate was filtered off, washed
with water, dried in air, recrystallized from
cyclohexane, and dried in a high vacuum. Yield 58 mg
(24%, calculated on the diaethylammonium salt), mp
5. Lovasz, T., Paizs, C., Cristea, I., and Irimie, F.D., Stud.
Univ. Babes-Bolyai, Chem., 1998, vol. 43, no. 2, p. 145;
Chem. Abstr., 2002, vol. 137, no. 247640h.
6. Vanderhaeghe, H. and Claesen, M., Bull. Soc. Chim.
Belg., 1959, vol. 68, no. 3, p. 30.
7. Matsukawa, S. and Ohta, B., J. Pharm. Soc. Jpn., 1949,
vol. 69, no. 4, p. 489; Chem. Abstr., 1950, vol. 44, p. 3455i.
8. Wheeler, H.L. and McFarland, D.F., Am. Chem. J.,
1909, vol. 42, no. 5, p. 431.
9. Erkin, A.V., Krutikov, V.I., and Chubraev, M.A., Russ. J.
Gen. Chem., 2004, vol. 74, no. 3, p. 423.
1
>120°C (decomp.), Rf 0.23 (A). H NMR spectrum
10. Pavlov, P.T., Goleneva, A.F., Lesnov, A.E., and Pro-
khorova, T.S., Khim.-Farm. Zh., 1998, vol. 32, no. 7,
p. 28.
(DMSO-d6), δ, ppm: 2.10 s (6H, Me), 2.40 s (6H, Me),
2.54 s (6H, Me), 5.11 s (1H, CH), 7.50 d (2H, Harom),
7.92 s (2H, CH), 8.12 d (2H, Harom), 11.56 br.s (2H,
OH).
11. Erkin, A.V., Krutikov, V.I., and Pavlovich, N.I., Russ. J.
Gen. Chem., 2003, vol. 73, no. 3, p. 463.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 2 2011