Modified synthesis of some 1-(pyrimidin-2-yl)-3-methyl-4-arylidenepyrazol- 5(4H)-ones

Article abstract of DOI:10.1007/s11176-008-2020-z

2-[3-Methyl-4(4-dialkylaminobenzylidene)-5-oxo-4,5-dihydropyrazol-1-yl] cyclopenta[d]pyrimidin-4(3H)-ones were synthesized by consecutive transformation of 2-hydrazinocyclopenta[d]pyrimidin-4(3H)-one prepared from benzylideneaminoguanidine and ethyl 2-oxocyclopentanoate.

Full text of DOI:10.1007/s11176-008-2020-z

ISSN 1070-3632, Russian Journal of General Chemistry, 2008, Vol. 78, No. 2, pp. 301 304.
Pleiades Publishing, Ltd., 2008.
Original Russian Text
A.V. Erkin, V.I. Krutikov, 2008, published in Zhurnal Obshchei Khimii, 2008, Vol. 78, No. 2, pp. 324 327.
Modified Synthesis of Some
-(Pyrimidin-2-yl)-3-methyl-4-arylidenepyrazol-5(4H)-ones
1
A. V. Erkin and V. I. Krutikov
St. Petersburg State Technological Institute,
Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: kruerk@yandex.ru
Received September 17, 2007
Abstract 2-[3-Methyl-4(4-dialkylaminobenzylidene)-5-oxo-4,5-dihydropyrazol-1-yl]cyclopenta[d]pyrimi-
din-4(3H)-ones were synthesized by consecutive transformation of 2-hydrazinocyclopenta[d]pyrimidin-4(3H)-
one prepared from benzylideneaminoguanidine and ethyl 2-oxocyclopentanoate.
DOI: 10.1134/S1070363208020205
The establishing of general rules of cyclization of
ethyl acetoacetate (6-methyl-4-oxo-3,4-dihydropyri-
midin-2-yl)hydrazone and aromatic aldehydes allowed
synthesis of a series of 2-(3-methyl-4-arylidene-5-oxo-
methylpyrimidin-4(3H)-one (I) [2] which inhibited
growth of Mycobacterium tuberculosis bacilliculture
by 100% at a concentration of 0.05 g l .
1
4
,5-dihydropyrazol-1-yl)-6-methylpyrimidin-4(3H)-
With the purpose to obtain potentially biologically
active analogs of compound I we synthesized 2-[4-(4-
dialkylaminobenzylidene)-3-methyl-5-oxo-4,5-di-
hydropyrazol-1-yl]cyclopenta[d]pyrimidin-4(3H)ones
IIa, IIb according to the scheme presented below.
ones [1] which proved to be suitable objects for
design of new antitubercular agents. The highest ac-
tivity in vitro was shown by 2-[4-(4-diethylaminoben-
zylidene)-3-methyl-5-oxo-4,5-dihydropyrazol-1-yl]-6-
O
O
NH2
HN
Ph
N
EtO
N
H
NH +
Ph
N
N
H
N
O
VIII
VI
VII
HCl
O
N
O
N
AcCH COOEt
HN
HN
2
N
H N
2
Me
N
N
H
H
OEt
O
IX
III
O
N
AcCHO
HN
N
Me
N
O
Ar
IIa, IIb
Ar = Me NC H (a), Et NC H (b).
2
6
4
2
6 4
301

302
ERKIN, KRUTIKOV
The synthesis of the key product, 2-hydrazinocyc-
lopenta[d]pyrimidin-4(3H)-one (III) by the reaction of
-thioxo-1,2-dihydrocyclopenta[d]pyrimidin-4(3H)-
one (IV) [3] or 2-(methylsulfanyl)cyclopenta[d]-
pyrimidin-4(3H)-one with hydrazine is associated with
significant difficulties. According to published data
aromatic aldehydes failed because of the strong tarring
of the reaction mixture. Heterocycles IIa, IIb are
1
2
easily identified by means of H NMR and UV spec-
1
troscopy. The H NMR spectra contain characteristic
proton signals of the cyclopentane fragment (2.0
2.8 ppm), aromatic ring (6.0 9.0 ppm), and ylidene
bond (7.6 ppm). In the visible part of the electronic
absorption spectra, there is a strong band at 495 nm
(log 4.40 4.80) related to electron transitions in the
branched conjugation system.
[
4], the synthesis of thioxoketone IV by cyclization
of thiourea with ethyl 2-oxocyclopentanoate proceeds
unsatisfactorily due to cleavage of the latter under the
conditions used, but it can be carried out through the
stage of preparation of an intermediate product, ethyl
2
-ureidocyclopentanoate, with the total yield of com-
EXPERIMENTAL
pound IV not exceeding 30 40%. In addition to that,
hydrazinolysis of thioether V instead of the expect
ed hydrazine gives an abnormal reaction product,
cyclopenta[c]pyrazol-5(4H)-one [5].
1
The H NMR spectra were taken on a Bruker WM-
400 spectrometer (400.13 MHz) in DMSO-d against
residual DMSO protons. The UV spectra were re-
6
corded on an SF-26 spectrophotometer in DMF (c
0
With the above data in mind, we prepared com-
pound III by an alternative procedure involving acid
hydrolysis of 2-(benzylidenehydrazino)cyclopenta[d]-
pyrimidin-4(3H)-one (VII) which, in its turn, was
obtained by cyclocondensation of benzylideneamino-
guanidine (VIII) with keto ester VI. Benzoylamino-
guanidine is less suitable for this purpose, because it
reacts with a suitable tricarbon component to form by-
product triazolo[4,3-a]pyrimidines through intramo-
lecular dehydration of initially formed 2-(benzoyl-
hydrazino)pyrimidines [6]. Unsubstituted amino-
guanidine is absolutely unsuitable due to its tendency
for cyclization with various -keto esters, leading to
derivatives of 1-carbamimidoylpyrazol-5(4H)-one,
.5 10 4 M). The individuality of the compounds
was controlled by TLC on Silufol UV-254 plates,
eluents 1:1:1 butanol-1 acetic acid water (system A)
and 2:1 acetone hexane (system B), development in
the UV and visible light. Elemental analysis was
carried out on Hewlett Packard B-185 and Leco
CHNS-932 analyzers.
Ethyl 2-oxocyclopentanoate (VI) was obtained by
cyclization of diethyl adipinate according to [9], and
diethyl adipinate was obtained by esterification of
adipic acid according to [10].
2
-[4-(4-Dimethylaminobenzylidene)-3-methyl-5-
oxo-4,5-dihydropyrazol-1-yl]cyclopenta[d]pyrim-
idin-4(3H)-one (IIa). A mixture of 0.5 g of hydra-
zone IX, 0.26 g of 4-(dimethylamino)benzaldehyde
and 0.1 g of potassium hydroxide was refluxed in
2
,3-diaminopyrimidin-4(3H)-one, or 3-amino-1,2,4-
triazole depending on reaction conditions [7].
Cyclocondensation of substituted guanidine VIII
and keto esterVI proceeds on heating under rigid
conditions in the absence of solvents. Subsequent
hydrolysis of benzylidenehydrazine VII with HCl
with simultaneous removal of liberated benzaldehyde
from the reaction zone gives hydrazine III. Note that
attempted preparation of compound III by boiling
benzylidenehydrazine VII with hydrazine hydrate in
ethanol according to the procedure in [8] failed: The
compound isolated from the reaction mixture was
chromatographically identical to starting compound
VII, and their mixed sample gave no melting point
depression.
1
5 ml of ethanol for 2 h. The suspension obtained was
cooled to room temperature, neutralized with acetic
acid, stirred for 15 min, and left for 2 days. The pre-
cipitate formed was filtered off, washed with ethanol,
and crystallized from DMF. After washing with di-
ethyl ether and drying in a vacuum 0.35 g (54%) of
compound IIa was obtained, mp 270 C (decomp.),
1
R 0.73(A). H NMR spectrum, , ppm: 2.01 m (2H,
f
CH ), 2.30 s (3H, Me), 2.65 t (2H, CH ), 2.75 t (2H,
2
2
CH ), 3.13 s (6H, NMe ), 6.84 d (2H, Ar), 7.64 s (1H,
2
2
CH), 8.53 d (2H, Ar), 11.96 br.s (1H, NH). UV spec-
trum, max, nm (log ): 595 (4.41). Found, %: C 66.84;
H 5.37; N 19.62. C H N O . Calculated, %: C 66.10;
2
0
21
5
2
Hydrazine III when reacted with ethyl acetoacetate
without a solvent forms ethyl acetoacetate (4-oxo-3,4-
dihydrocyclopenta[d]pyrimidin-2-yl)hydrazone (IX)
whose treatment with 4-(dialkylamino)benzaldehydes
in ethanol in the presence of potassium hydroxide
gives target heterocycles IIa, IIb. The synthesis of
compounds IIa, IIb by the three-component con-
densation of hydrazine III, ethyl acetoacetate, and
H 5,82; N 19.27.
2-[4-(4-Diethylaminobenzylidene)-3-methyl-5-
oxo-4,5-dihydropyrazol-1-yl]cyclopenta[d]pyrim-
idin-4(3H)-one (IIb). A mixture of 0.5 g of hydra-
zone IX, 0.32 g of 4-(diethylamino)benzaldehyde, and
0.1 g of potassium hydroxide was refluxed for 2 h in
15 ml of ethanol. The suspension obtained was cooled
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 2 2008

MODIFIED SYNTHESIS OF SOME 1-(PYRIMIDIN-2-YL)-3-METHYL-...
303
to room temperature, neutralized with acetic acid,
stirred for 15 min, and left for 2 days. The suspension
obtained was evaporated in a vacuum to dryness, the
residue was triturated with 20 ml of water, and the
precipitate was filtered off and dried in a vacuum over
phosphorus pentoxide. The dry product was crystal-
lized from DMF, washed with diethyl ether, and dried
with under vigorous stirring. The solution obtained
was filtered, and 53 g of freshly distilled benzalde-
hyde dissolved in 50 ml of ethanol was added drop-
wise to the filtrate under vigorous stirring. After the
addition was complete, the mixture was stirred ad-
ditionally for 1 h, and the precipitate the formed was
filtered off, crystallized from water, and dried at 70 C
for 10 h to give 51.5 g (64%) of compound VIII, mp
in a vacuum to give 0.19 g (27%) of compound IIb,
1
mp 229 C (decomp.), R 0.80 (A). H NMR spectrum,
182 C (published data: 178 C [11]), R 0.77 (A).
f
f
,
ppm: 1.22 t (6H, Me), 2.03 m (2H, CH ), 2.12 s
3
Ethyl acetoacetate (4-oxo-3,4-dihydrocyclo-
penta[d]pyrimidin-2-yl)hydrazone (IX). Hydrazine
III hydrochloride, 1.6 g, was added to a solution of
(
(
(
3H, Me), 2.62 t (2H, CH ), 2.77 t (2H, CH ), 3.57 m
4H, CH ), 6.82 d (2H, Ar), 7.60 s (1H, CH), 8.53 d
2H, Ar), 12.02 br.s (1H, NH). UV spectrum, max,
2 2
2
0
.44 g of potassium hydroxide in 25 ml of absolute
nm (log ): 495 (4.74). Found, %: C 67.31; H 5.93; N
7.95. C H N O . Calculated, %: C 67.50; H 6.44;
ethanol. The mixture was refluxed for 30 min and
evaporated in a vacuum to dryness. The residue was
triturated with 15 ml of water, the precipitate was
filtered off, washed with water, and dried in a vacuum
over phosphorus pentoxide to give 0.92 g (70%) of
hydrazine III as a free base which was used in the
next step without additional purification. A mixture
of 0.92 g of hydrazine III and 0.79 g of ethyl aceto-
acetate was kept at 100 C for 30 min. The precipitate
was crystallized from acetonitrile and dried in a
1
2
2
25
5
2
N 17.89.
2
-Hydrazinocyclopenta[d]pyrimidin-4(3H)-one
(
III)). Through a suspension of 5.08 g of benzyl-
idenehydrazine VII in dilute (1:1) hydrochloric acid
heated to 90 C, a stream of steam until a solution
formed. It was filtered hot and evaporated to dryness
in a vacuum. The residue was triturated with 30 ml of
absolute ethanol, and the precipitate was filtered off
and washed with ethanol. Drying in a vacuum over
phosphorus pentoxide gave 2.36 g (58%) of com-
vacuum over phosphorus pentoxide to give 0.85 g
1
(
55%) of compound IX, mp 147 C, R 0.81 (A). H
f
pound III, mp > 230 C (decomp.), R 0.53 (A). An
NMR spectrum, , ppm: 1.25 m (3H, OCH Me0),
f
2
1
2
.89 s (2H, CH ), 1.96 s (3H, Me), 2.54 t (2H, CH ),
2 2
analytical sample was prepared by crystallization from
1
.64 t (2H, CH ), 3.35 s (2H, CH ), 4.11 m (2H,
ethanol. H NMR spectrum, , ppm: 1.97 m (2H,
2
2
OCH Me), 9.85 br.s (1H, NH), 11.07 br.s (1H, NH).
CH ), 2.54 t (2H, CH ), 2.79 t (2H, CH ), 8.89 br.s
2
3
2
2
+
Found, %: C 55.88; H 6.36; N 20.04. C H N O .
(
5H, NH , 2NH, N H). Found, %: C 42.59; H 5.75;
13 18
4
3
2
Calculated, %: C 56.11, H 6.47; N 20.14.
N 28.72. C H N O HCl. Calculated, %: C 41.48;
7
10
4
H 5.43; N 27.65. Isolated as hydrochloride.
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2
-(Benzylidenehydrazino)cyclopenta[d]pyrim-
1
2
. Erkin, A.V., Krutikov, V.I., and Chubraev, M.A., Zh.
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idine VIII and 23.6 g of ethyl 2-oxocyclopentanoate
VI) was heated at 150 C under vigorous stirring for
(
3
. Erkin, A.V. and Krutikov, V.I., Abstracts of Papers,
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triturated with 500 ml of water, the precipitate was
filtered off, washed with water, and dried in a stream
of warm air for 10 h. The dry product was crystallized
from acetic acid, washed with water, and dried at
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mp 245 C (decomp.), R 0.55 (B). H NMR spectrum,
ppm: 1.93 m (2H, CH ), 2.54 s (2H, CH ), 2.63 s
2H, CH ), 7.37 m (3H, Ph), 7.90 s (2H, Ph), 8.00 s
1H, NH), 11.22 br.s (2H, NH, N=CH). Found, %:
C 65.19; H 6.72; N 18.82. C H N O. Calculated,
7
3
4
5
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(
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4
14
4
%
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1
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6
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1
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5
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