Synthesis of 2-(pyrazol-1-yl)pyrimidine derivatives by cyclocondensation of ethyl acetoacetate (6-methyl-4-oxo-3,4-dihydropyrimidin-2-yl)hydrazone with aromatic aldehydes

Article abstract of DOI:10.1023/B:RUGC.0000030401.30369.4d

2-(4-Arylidene-3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)-6-methylpyrimidin- 4(3H)-ones were obtained by reaction of ethyl acetoacetate (6-methyl-4-oxo-3,4- dihydropyrimidin-2-yl)hydrazone with aromatic aldehydes. Successful cyclization occurs with aldehydes containing an auxochromic substituent in the para position.

Full text of DOI:10.1023/B:RUGC.0000030401.30369.4d

Russian Journal of General Chemistry, Vol. 74, No. 3, 2004, pp. 423 427. Translated from Zhurnal Obshchei Khimii, Vol. 74, No. 3, 2004,
pp. 466 471.
Original Russian Text Copyright
2004 by Erkin, Krutikov, Chubraev.
Synthesis of 2-(Pyrazol-1-yl)pyrimidine Derivatives
by Cyclocondensation of Ethyl Acetoacetate
(
6-Methyl-4-oxo-3,4-dihydropyrimidin-2-yl)hydrazone
with Aromatic Aldehydes
A. V. Erkin, V. I. Krutikov, and M. A. Chubraev
St. Petersburg State Institute of Technology, St. Petersburg, Russia
Received Januray 16, 2003
Abstract 2-(4-Arylidene-3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)-6-methylpyrimidin-4(3H)-ones
obtained by reaction of ethyl acetoacetate (6-methyl-4-oxo-3,4-dihydropyrimidin-2-yl)hydrazone with aro-
matic aldehydes. Successful cyclization occurs with aldehydes containing an auxochromic substituent in the
para position.
were
2
-(Pyrazol-1-yl)pyrimidines form an abundant class
of heterocyclic compounds possessing antitubercular
1], antibacterial and antiviral [2], as well as antitumor
synthetic precursor of Mebron, 6-methyl-2-(3-methyl-
5-oxo-4,5-dihydropyrazol-1-yl)pyrimidin-4(3H)-one
(VI) whose reactions with aromatic [5] or heterocyclic
[6] aldehydes are known to provide the corresponding
4-ylidene derivatives. It was found that 2-(4-arylidene-
3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)-6-methyl-
pyrimidin-4(3H)-ones Va Vf are readily formed by
condensation of ethyl acetoacetonate (6-methyl-4-oxo-
[
properties [3]. The best known medicinal of this series
is Mebron (Mepyryzol) [4-methoxy-6-methyl-2-(5-
methoxy-3-methylpyrazol-1-yl)pyrimidine] used in
treatment of acute inflammatory infections [4]. At the
same time, the strong but short-term effect of Mebron
necessitates search for its more effective analogs.
3,4-dihydropyrimidin-2-yl)hydrazone
(IV)
with
aromatic aldehydes in the presence of alkali by
Scheme 1.
To this end, we undertook a modification of the
Scheme 1.
O
N
O
O
HN
Me2SO4
HN
(H2N)2
HN
H NNH
S
Me
MeS
N
Me
N
Me
2
H
I
II
III
MeCOCH COOEt
2
O
O
N
HN
HN
N
Me
Ar
Me
N
O
N
Me
N
N
Me
ArCHO
H
OEt
O
IV
Va Vf
Ar = 4-Me NC H (a), 4-Et NC H (b), 3-MeO-4-HOC H (c), 3-EtO-4-HOC H (d), 3-MeO-4-HO-5-ClC H (e),
2
6
4
2
6
4
6
3
6
3
6 2
3
-MeO-4-HO-5-BrC H (f).
6 2
1
070-3632/04/7403-0423 2004 MAIK Nauka/Interperiodica

424
ERKIN et al.
Table 1. Yields, melting points, TLC data, and elemental analyses of arylidenepyrazolones Va Vf
Found, %
H
Calculated, %
mp,
solvent for
crystallization)
C
Comp. Yield,
Rf
(I )
(
Formula
no.
%
C
N
C
H
N
Va
Vb
Vc
Vd
Ve
Vf
32
37
66
28
55
47
255 (decomp.) (DMF)
202 (decomp.) (MeCOMe) 0.49 65.36 6.03 18.95
>300 (DMF MeOH)
>300 (DMF MeOH)
>300 (DMF)
0.47 63.37 5.82 20.47
C H N O
64.09 5.64 20.77
65.75 6.30 19.17
60.00 4.71 16.47
61.01 5.08 15.82
54.47 4.01 14.95
48.69 3.58 13.37
1
8
19
5
2
2
4
4
C H N O
20 23 5
0.19 59.80 4.59 16.21
0.23 60.73 4.93 15.65
0.21 54.27 3.85 14.81
0.24 48.45 3.39 13.19
C H N O
17 16 4
C H N O
1
8 18 4
C H ClN O
1
7
15
4 4
>300 (EtOH)
C H BrN O
17 15 4 4
Hydrazone IV was prepared by S-methylation of
-methylthiouracil I with dimethyl sulfate, followed
solvent by short heating of the reaction mixture at
100 C.
6
by hydrazinolysis of 6-methyl-2-(methylsulfanyl)-
pyrimidin-4(3H)-one (II) and treatment of 2-hydra-
zino-6-methylpyrimidin-4(3H)-one (III) with ethyl
acetoacetate. Direct hydrazinolysis of thioxoketone I
in boiling ethanol provides little hydrazine III [7],
whereas heating of thoether II with hydrazine hydrate
for 6 60 h in ethanol [8, 9] provides compound III in
reasonable yields. We found that reasonable (up to
Of the published conditions for pyrazole ring
closure in hydrazine IV and related compounds [11]
we considered the most appropriate alkaline catalysis
which prevents hydrolysis of the target products to
6-methyluracil. We found that when heated with
equimolar amounts of aldehydes and potassium hydr-
oxide in absolute methanol hydrazone IV undergoes
cyclization to form arylidenepyrazolones Va Vf. The
products are colored high-melting compounds. Their
physicochemical properties are given in Table 1.
4
5%) yields of hydrazine III can be attained by re-
fluxing thioether II with excess hydrazine hydrate in
-propanol for 2 h (method a). At shorter reaction
2
times, a low (no higher than 14%) conversion of thio-
ether II is observed, whereas at longer reaction times,
much by-products are formed.
Structural assessment of arylidenepyrazolones
Va Vf was made on the basis of a characteristic
1
ylidene proton signal at 6.9 7.7 ppm in their H NMR
Baumbach et al. [10] have reported the reaction of
thioether II with hydrazine hydrate in the absence of
solvent. The reaction involved no recyclization of the
pyrimidine ring into pyrazole, and compound II
smoothly converted into hydrazine III. Actually, upon
heating of thioether II with excess hydrazine hydrate
at 100 C for no more than 30 min (method b) we
isolated hydrazine III in a yield higher than 70%. The
product was chromatographically identical to the
sample of hydrazine III, synthesized by method a,
and was identified as a benzylidene derivative.
spectra (Table 2).
It should be noted that the cyclization of hydrazone
IV into arylidenepyrazolones Va Vf is successful
only if an auxochromic substituent is present in the
para position of the aldehyde to stabilize the target
products via conjugation of its lone electron pairs with
aromatic
electrons. With aldehydes containing no
such a substituent, 4,4 -bispyrazolylmethanes are
formed. Thus, the reaction of hydrazone IV with
benzaldehyde gives, according to H NMR data, bis-
1
The condensation of hydrazine III with ethyl
acetoacetate we also performed in the absence of
[5-hydroxy-3-methyl-1-(6-methyl-4-oxo-3,4-dihydro-
pyrimiden-2-yl)pyrazol-4-yl]phenylmethane (VII).
Ph
Me
Me
Me
N
N
N
OH HO
O
PhCHO
N
N
PhCHO
N
IV
2
HN
N
N
NH
N
NH
O
Me Me
O
Me
O
VII
VI
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 74 No. 3 2004

SYNTHESIS OF 2-(PYRAZOL-1-YL)PYRIMIDINE DERIVATIVES
Table 2. 1H NMR spectra of arylidenepyrazolones Va Vf
425
Comp.
Va
, ppm
2.21 s (3H, Me), 2.31 s (3H, Me), 3.18 s (6H, NMe ), 5.94 s (1H, CH), 6.82, 6.87 d (2H, Ar), 7.63 s (1H, CH),
a
2
8
.51, 8.55 d (2H, Ar)
Vb
1.17, 1.21, 1.25 t (6H, NCH Me), 2.20 s (3H, Me), 2.32 s (3H, Me), 3.51, 3.55, 3.59, 4.01 q (4H, NCH Me),
2
2
a
6
.03 (1H, CH), 6.83, 6.87 d (2H, Ar), 7.65 s (1H, CH), 8.51, 8.55 d (2H, Ar)
a
Vc
2.19 s (3H, Me), 2.21 s (3H, Me), 3.73 s (3H, OMe), 5.84 s (1H, CH), 6.14, 6.19 d (1H, Ar), 6.97 s (1H, CH),
.62, 8.38 d (2H, Ar), 13.05 s (1H, OH)
1.36, 1.40, 1.43 t (3H, OCH Me), 2.20 s (3H, Me), 2.21 s (3H, Me), 3.96, 3.98, 4.01, 4.05 q (4H, OCH Me),
7
Vd
2
2
a
5
.82 s (1H, CH), 6.18, 6.22 d (1H, Ar), 6.97 s (1H, CH), 7.63, 8.35 d (2H, Ar), 12.99 s (1H, OH)
a
Ve
2.20 s (3H, Me), 2.23 s (3H, Me), 3.76 s (3H, OMe), 5.83 s (1H, CH), 7.09 s (1H, CH), 8.21 br.s (2H, Ar),
2.78 s (1H, OH)
2.20 s (3H, Me), 2.22 s (3H, Me), 3.74 s (3H, OMe), 5.85 s (1H, CH), 7.10 s (1H, CH), 8.24 br.s (2H, Ar),
2.81 s (1H, OH)
1
a
Vf
1
a
Pyrimidine methine proton signals.
The spectrum of phenylmethane VII contains a
signal of the exocyclic methine proton at 5.04 ppm,
and the integral intensity ratio of the methyl and
phenyl proton signals is 12:5. The structure of com-
pound VII was confirmed by its independent syn-
thesis from pyrazolone VI and benzaldehyde at a 2:1
molar ratio.
solutions of compound Va contains a broad strong
band at 430 520 nm ( max 27000) and a weak band
at 350 400 nm ( max 3000). Taking into account
that pyrazolone VI is incapable of absorbing visible
light [12] we can assign the first band to the
*
transition on the direct conjugation chain, whereas the
fact that the second band is weak and smoothens in
acidic solution (curve 1) relates it to the n
tion from the nitrogen lone electron pair to the aroma-
tic ring. In combination with the enhanced intensity of
transi-
The role the auxochromic substituent plays in
stabilization of arylidenepyrazolones Va Vf is illu-
strated by the UV spectra of 6-methyl-2-[4-(4-di-
methylaminobenzylidene)-3-methyl-5-oxo-4,5-di-
hydropyrazol-1-yl]pyrimidin-4(3H)-one (Va) (Fig. 1).
The spectra of neutral (curve 2) and alkaline (curve 3)
the
* band, the smoothening of the n
* band
of pyrazolone Va in acidic solution can be explained
in terms of formation of protonated form A.
Me
Me
N+
N
O
OH
Me
Me
A
The vibrational structure of the
* band, which
chemical shifts were measured relative to residual
DMSO proton signals.
is preserved in the spectra of acidic, neutral, and
alkaline solutions of compound Va, points to a weak
overlap of the electronic clouds of its chromophores
and thus to nonplanarity of the molecule. Actually, the
Fletcher Reeves quantum-chemical geometry opti-
mization of molecule Va showed that the phenyl ring
plane is drawn out of the pyrazole ring plane by 40.8 ,
and the angle between the pyrazole and pyrimidine
ring planes is 54.5 (Fig. 2).
The UV spectra were recorded on an SF-26 spec-
4
trophotometer in methanol solutions (c 1 10 M).
The purity of the compounds was proved by TLC
on Silufol UV-254 plates in the following systems:
acetone hexane, 2:1 (A); acetone hexane, 2:1, plus 2
drops of conc. HCl (B); chloroform methanol, 9:1
(C); and chloroform methanol, 5:1 (D); development
in UV light.
EXPERIMENTAL
The Fletcher Reeves quantum-chemical geometry
optimization was performed using the HYPERCHEM
program package (Ver. 6.03).
1
The H NMR spectra were obtained on a Bruker
AC-200 instrument (200.13 MHz) in DMSO-d , the
6
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 74 No. 3 2004

426
ERKIN et al.
,
l mol 1 cm 1
0000
,
l mol 1 cm 1
500
3
2
1
3
2
3
5000
0000
5000
0000
000
1
3
000
2
2
2
2
1
500
000
500
3
1
1
5
3
40
360
380
420
440
nm
420 440
460
480
500
520
, nm
,
Fig. 1. Visible electronic absorption spectra of arylidenepyrazolone Va in mixed solvents. (1) MeOH HCl, 1:1; (2) MeOH;
and (3) MeOH KOH, 1:1.
2
.06 s (3H, Me), 5.60 s (1H, CH), 12.15 s (2H, NH).
Found N, %: 19.47. C H N OS. Calculated N, %:
5
6
2
1
9.71.
6
-Methyl-2-(methylsulfanyl)pyrimidin-4(3H)-
one (II). Dimethyl sulfate, 7.1 g, was added to a solu-
tion of 8.0 g of thioxoketone I in 45 ml of water
containing 5 g of NaOH. The mixture was heated on
a boiling water bath for 3 h and then cooled to room
temperature and acidified with dilute (1:1) hydro-
chloric acid to a stable weakly acidic reaction. The
precipitate that formed was filtered off and purified by
reprecipitation with dilute (1:1) HCl from 10%
aqueous NaOH. The precipitate was washed with cold
water and dried in a vacuum over P O . Yield 7.2 g
2
5
(
2
82%), R 0.47 (A), mp 228 C (published data: mp
f
25 C [13]).
-Hydrazino-6-methylpyrimidin-4(3H)-one
III). a. A mixture of 1.56 g of thioester II and 1.5 g
2
(
Fig. 2. Molecular geometry of arylidenepyrazolone Va,
optimized by the Fletcher Reeves method (carbon atoms
are gray-colored, hydrogen atoms are not shown).
of hydrazine hydrate in 50 ml of 2-propanol was re-
fluxed for 2 h. After cooling, the precipitate was
filtered off, recrystallized from water, and dried in a
vacuum over P O . Yield 0.62 g (45%).
2
5
6
-Methyl-2-thiouracil (I). Freshly distilled ethyl
b. A mixture of 1.56 g of thioether II and 1.5 g of
hydrazine hydrate was heated on a boiling water bath
for 30 min. After cooling, the suspension was diluted
with 5 ml of water, the precipitate was filtered off,
recrystallized from water, and dried in a vacuum over
P O . Yield 1 g (71%), R 0.14 (B), mp >235 C
acetoacetate, 36.4 g, was added to a solution of
sodium ethoxide, prepared from 6.5 g of sodium and
00 ml of 96% ethanol. The resulting solution was
heated to 60 C, and 21.6 g of crystalline thiourea was
added at that temperature with vigorous stirring. A
suspension formed and was refluxed for 3 h. After
cooling, the precipitate was filtered off, dissolved in
1
2
5
f
(decomp.).
2
2
00 ml of water, and acidified with conc. HCl to pH
. The precipitate was filtered off, washed with cold
2-(Benzylidenehydrazino)-6-methylpyrimidin-
4(3H)-one was prepared from hydrazine III and
water, and dried at 100 C for 6 h. Yield 20.5 g (51%),
benzaldehyde. Yield 0.77 g (68%), R 0.39 (C), mp
237 C (i-PrOH) (published data: mp 228 229 [9],
f
1
R 0.54 (A), mp >300 C. H NMR spectrum, , ppm:
f
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 74 No. 3 2004

SYNTHESIS OF 2-(PYRAZOL-1-YL)PYRIMIDINE DERIVATIVES
427
1
2
(
35 237 C [14]). H NMR spectrum, , ppm: 2.09 s
acid from 10% aqueous NaOH, washed with water,
and dried in a vacuum over P O . Yield 0.19 g (25%),
3H, Me), 5.48 s (1H, CH), 7.36, 7.87, 7.89 m (5H,
Ph), 8.03 s (1H, NHe), 11.20 br.s (2H, CH + NH).
2
5
1
R 0.19 (D), mp > 290 C (decomp.). H NMR spec-
f
trum, , ppm: 2.09 s (6H, Me), 2.21 s (6H, Me),
Ethyl acetoacetate (6-methyl-4-oxo-3,4-dihydro-
pyrimidin-2-yl)hydrazone (IV). A mixture of 0.7 g
of hydrazine III and 0.78 g of ethyl acetoacetate was
heated on a boiling water bath for 10 min. After
cooling, the reaction mixture solidified and was
ground, recrystallized from 2-propanol, and dried in a
vacuum over P O . Yield 58 g (46%), R 0.19 (B), mp
4
.79 s (1H, CH ), 5.86 s (2H, CH), 7.22 m (5H, Ph).
e
Found, %: C 59.47; H 4.61; N 22.05. C H N O .
2
5
24
8
4
Calculated, %: C 60.00; H 4.80; N 22.40.
ACKNOWLEDGMENT
2
5
f
The authors express their gratitude to G.V. Erkin
for performing analytical experiments.
1
47 C (published data: mp 148 C [15]).
-[4-(4-Dimethylaminobenzylidene)-3-methyl-5-
oxo-4,5-dihydropyrazol-1-yl]-6-methylpyrimidin-
2
REFERENCES
4(3H)-one (Va). A mixture of 0.76 g of hydrazone IV,
0
.45 g of 4-(dimethylamino)benzaldehyde and 0.17 g
1. US Patent 3040047, 1962, Chem. Abstr., 1963,
vol. 58, P533e.
2. Jpn. Patent 7443985, 1974, Chem. Abstr., 1974,
vol. 81, P49699w.
of KOH in 10 ml of absolute methanol was refluxed
for 3 h, neutralized with glacial acetic acid, and
cooled to 0 C. The precipitate that formed was filtered
off, recrystallized from absolute DMF, and dried in a
3
. Naito, H., Sugimori, M., Mitsui, I., Nakamura, Y.,
Iwahawa, M., Ishii, M., Hirotani, K., Kumazawa, E.,
and Ejima, A., Chem. Pharm. Bull., 1999, vol. 47,
no. 12, p. 1679.
vacuum over P O .
2
5
Compounds Vb Vf were prepared in a similar way
and isolated by reduction of the reaction mixture by
half, dilution of the residue with three volumes of
water (Vb) or filtration after acidification (Vc Vf),
recrystallization from appropriate absolute solvent
4
. Shvarts, G.Ya., Khim.-Farm. Zh., 1980, vol. 14, no. 9,
p. 22.
5. Cristea, I., Stud. Univ. Babes-Bolyai, Chem., 1988,
(
Table 1), and drying over P O .
vol. 33, no. 2, p. 61.
2
5
6
. Panea, I. and Cristea, I., Stud. Univ. Babes-Bolyai,
Chem., 1996, vol. 41, no. 1, p. 9.
6
-Methyl-2-(3-methyl-5-oxo-4,5-dihydropyrazol-
1
-yl)pyrimidin-4(3H)-one (VI). A mixture of 1.26 g
of hydrazone IV and 0.28 g of KOH in 15 ml of ab-
solute methanol was refluxed for 3 h. After cooling,
the reaction mixture was neutralized with glacial
acetic acid, the precipitate was filtered off, and the
filtrate was reduced in a vacuum until crystallization
began. The precipitates were combined, recrystallized
from water, and dried in a vacuum over P O . Yield
7. Libermann, D. and Rouaix, A., C. R. Acad. Sci., 1955,
vol. 240, no. 9, p. 984.
8. Vanderhaeghe, H. and Claesen, M., Bull. Soc. Chim.
Belg., 1959, vol. 68, no. 3, p. 30.
9
. Brady, L.E. and Herbst, R.M., J. Org. Chem., 1959,
vol. 24, no. 7, p. 922.
2
5
1
1
1
1
1
0. Baumbach, F., Henning, H.-G., and Hilgetag, G.,
0
.67 g (65%), R 0.39 (D), mp 204 C (published data:
mp 203 C [15]).
f
Z. Chem., 1964, vol. 4, no. 2, p. 67.
1. Ivashchenko, A.V. and Garicheva, O.N., Khim.
Geterotsikl. Soedin., 1982, no. 5, p. 579.
Bis[5-hydroxy-3-methyl-1-(6-methyl-4-oxo-3,4-
dihydropyrimidin-2-yl)pyrazol-1-yl]phenylmethane
VII) (independent synthesis). A mixture of 0.62 g of
pyrazolone VI, 0.16 g of benzaldehyde, and 0.08 g of
KOH in 10 ml of absolute methanol was refluxed for
2. Baldea, I., Ghirisan, A., Silberg, I.A., and Cristea, I.,
(
Rev. Roum. Chim., 1997, vol. 42, no. 9, p. 767.
3. Simon, I.B. and Kovtunovskaya, I.I., Zh. Obshch.
Khim., 1951, vol. 21, no. 4, p. 760.
3
h. After cooling, the reaction mixture was neutra-
4. Claesen, M. and Vanderhaeghe, H., Bull. Soc. Chim.
Belg., 1959, vol. 68, no. 3, p. 47.
lized with glacial acetic acid, methanol was evapo-
rated by half, and the residue was diluted with two
volumes of water and triturated until crystallized. The
precipitate was filtered off, reprecipitated with acetic
15. Cristea, I. and Farcasan, V., Rev. Chim., 1987, vol. 38,
no. 8, p. 674.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 74 No. 3 2004