Reaction of 6-methyl-2-(2-oxo-2-phenyl-ethylidene)-2,3-dihydropyrimidin- 4(1H)-one with hydrazine and hydroxylamine

Article abstract of DOI:10.1007/s10593-013-1162-z

The reaction of 6-methyl-2-(2-oxo-2-phenylethylidene)-2,3-dihydropyrimidin- 4(1H)-one and of its nitrosation product with hydroxylamine stops at the stage of forming the corresponding oximes. The reaction of 6-methyl-2-(2-oxo-2- phenylethylidene)-2,3-dihydropyrimidin-4(1H)-one with hydrazine yields a mixture of 3-amino-5-phenylpyrazole and 3-methyl-2-pyrazolin-5-one in 71 and 62% yields, respectively. The ketoxime is used in the synthesis of a series of imidazole N(3)-oxides substituted at the 1, 4, and 5 positions of the imidazole ring.

Full text of DOI:10.1007/s10593-013-1162-z

Chemistry of Heterocyclic Compounds, Vol. 48, No. 10, January, 2013 (Russian Original Vol. 48, No. 10, October, 2012)
REACTION OF 6-METHYL-2-(2-OXO-2-PHENYL-
ETHYLIDENE)-2,3-DIHYDROPYRIMIDIN-4(1H)-ONE
WITH HYDRAZINE AND HYDROXYLAMINE
A. A. Yavolovskii1, L. V. Grishchuk1, I. M. Rakipov1, D. E. Stepanov1,
Yu. E. Ivanov1*, and G. L. Kamalov1
The reaction of 6-methyl-2-(2-oxo-2-phenylethylidene)-2,3-dihydropyrimidin-4(1H)-one and of its
nitrosation product with hydroxylamine stops at the stage of forming the corresponding oximes. The
reaction of 6-methyl-2-(2-oxo-2-phenylethylidene)-2,3-dihydropyrimidin-4(1H)-one with hydrazine
yields a mixture of 3-amino-5-phenylpyrazole and 3-methyl-2-pyrazolin-5-one in 71 and 62% yields,
respectively. The ketoxime is used in the synthesis of a series of imidazole N(3)-oxides substituted at the
1, 4, and 5 positions of the imidazole ring.
Keywords: hydrazine, hydroxylamine, imidazole N-oxides, pyrazoles, pyrimidine oximes, pyrimidines,
pyrimidine ring transformation.
It is known that the interaction of hydrazines with pyrimidines depending on the structure of the
reagents and the reaction conditions can be a convenient method for preparing 2-, 4(6)-hydrazinopyrimidines
[1-3]. It can also lead to transformation of a pyrimidine ring to a pyrazole cyclic system [4-8].
O
H
N
O
N
R2
N
R1
a
R
O
N
O
R2
CHO
N
R2
CH
=N–NHR
NH2NHR
N
O
N
R1
O
N
R1
O
H
O
b
N
R1
N
R2
N
R
N
_______
*To whom correspondence should be addressed, e-mail: ivanov_yu@ukr.net.
1A. V. Bogatsky Physico-Chemical Institute, National Academy of Sciences of Ukraine, 86 Lyustdorfskaya
Road, Odessa 65080, Ukraine
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1598-1602, October, 2012.
Original article submitted November 27, 2011.
0009-3122/13/4810-1487©2013 Springer Science+Business Media New York
1487

The usual mechanism for conversion of pyrimidines to pyrazoles involves nucleophilic attack of a
hydrazine molecule at the C-4 and C-6 atoms of the pyrimidine followed by loss of the N(1)–C(2)–N(3)
fragment [4, 5]. The presence of a substituent containing a carbonyl group in the pyrimidine ring can change the
reaction course. Thus, 5-formyluracils react with hydrazines to give pyrazole-4-carboxylic acid ureides [8]
which implies the intermediate formation of a formylhydrazone with subsequent intramolecular attack by the
terminal amino group on the C-6 atom of the pyrimidine (route b). Formation of pyrazolin-5-one derivatives
(route a) through reaction of 5-formyluracil with hydrazine was not observed.
Continuing studies of the reaction of pyrimidines with nitrogen-containing nucleophiles [2, 3, 9-11] we
have examined the interaction of 6-methyl-2-(2-oxo-2-phenylethylidene)-2,3-dihydropyrimidin-4(1H)-one (1)
with hydrazine and with hydroxylamine.
H
N
N
O
H
N
N
NH2
Ph
HN
NH
2
Ph
N2H4
+
Me
O
N
H
H
N
H
N
H2N
N
Ph
NH2
Me
Me
O
O
A
B
3
N2H4
O
O
O
HN
Ph
HN
HN
HNO2
RNH2
N
AcOH HON
H2O
N
Me
(CH2O)n
AcOH
N
Me
N
H
Me
N
4
O
Ph
O
Ph
1
R
7a–d
EtOH
Py
KOH
H2O
H2NOH
HN
H2NOH
O
O
HN
HON
N
Me
N
Me
Ph
NOH
Ph
NOH
6
5
7 a R = Me, b R = (CH2)2OH, c R = CH2COOH, d R = (CH2)2COOH
We have found that reaction of pyrimidine 1 with an excess of hydrazine in refluxing ethanol gives a
mixture of 3-amino-5-phenylpyrazole (2) [12] and 3-methyl-2-pyrazolin-5-one (3) [13, 14].
The formation of pyrazoles 2, 3 from pyrimidine 1 containing a -oxoethylidene fragment at the
position 2 is theoretically possible through several routes. However, in our view, the most likely of these is the
formation of hydrazone A with subsequent addition of its NH2 fragment at the pyrimidine ring C-2 atom and
opening of the six-membered ring. Then hydrazinolysis occurs, followed by cyclization of the 3-amino-
5-phenylpyrazole derivative B to the pyrazoles 2 and 3.
Treatment of pyrimidine 1 and its nitrosation product 4 with excess hydroxylamine in either neutral or
basic medium stops at the stage of formation of the monooxime 5 or the dioxime 6, respectively.
The ketoxime 4 was used by us for the preparation of a series of imidazole N(3)-oxides 7a-d which are
substituted at the positions 1, 4, and 5 of the imidazole ring. The transformation of oxime 4 to imidazole 7 was
achieved using a mixture of paraformaldehyde and the corresponding monosubstituted amine (methylamine,
1488

ethanolamine, glycine, or -alanine). Condensation was carried out by short heating of the components in acetic
acid. It was not possible to achieve this reaction using -alanine, serine, and a series of other natural amino
acids. Hence it should be noted that formation of the imidazole N-oxides from ketoxime 4 demands more
forcing conditions when compared with similar reactions of 1,2-dialkyl- and 1,2-diphenylketoximes [15]. The
influence of steric factors also proved significant in our case.
1
The structure of the synthesized compounds was established using mass spectrometry and H NMR
spectroscopy.
Hence it has been shown that the basic route, how 6-methylpyrimidin-4-one containing a -oxo-
ethylidene fragment at the position 2 interacts with hydroxylamine and hydrazine, is a substitution of the
carbonyl oxygen (in the case of hydrazine, the reaction proceeds with subsequent destruction of the pyrimidine
fragment). Simple methods are proposed for modification of the β-oxoethylidene fragment, to give the
corresponding oxime, dioxime, and ketoxime which can serve as promising starting compounds in the synthesis
of a series of noncondensed biheterocyclic systems.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian WPX-300 spectrometer (300 MHz) using DMSO-d6 with
TMS as internal standard. Mass spectra were recorded on an MX 1321 instrument using direct introduction of
the sample at an electron impact ionization energy of 70 eV and ion source temperature of 220°C. Melting
points were determined on a PTP (TU 25-11-1144-76) apparatus in sealed and open capillaries at a heating rate
of 4-6°C/min and 1-2°C/min near the melting point. The purity of the synthesized compounds was monitored by
TLC on Silufol UV-254-VIS plates with MeOH–MeCN–CHCl3 (1:3:7) as eluent.
The starting 6-methyl-2-(2-oxo-2-phenylethylidene)-2,3-dihydropyrimidin-4-(1H)-one (1) was synthe-
sized by method [16].
3-Amino-5-phenylpyrazole (2) and 3-Methyl-2-pyrazolin-5-one (3). Compound 1 (1.00 g, 4.4 mmol)
was dissolved in a minimal amount of refluxing EtOH (90-100 ml), and hydrazine hydrate (20 ml, 400 mmol)
was added. The mixture was refluxed for 7 h and filtered. The filtrate was evaporated on a rotary evaporator.
The oily residue was extracted with boiling benzene (4×20 ml). The crystals of compound 2 precipitated from
the benzene were filtered off and dried in vacuo. Yield 0.50 g (71%). Colorless crystals; mp 124-127°C (mp
127°C (C6H6) [12]). 1H NMR spectrum, , ppm: 11.77 (1H, s, NH); 7.66-7.26 (5H, m, H Ph); 5.76 (1H, s, H-4);
4.80 (2H, s, NH2). Mass spectrum, m/z (Irel, %): 159 [M]+ (100), 130 (16), 102 (10), 77 (17). Found, %: C 68.00;
H 5.74; N 26.46. C9H9N3. Calculated, %: C 67.91; H 5.70; N 26.40. The residue insoluble in benzene was
extracted with refluxing MeCN (6×20 ml), and the extract was evaporated to the start of crystallization. The
precipitated pyrazolone 3 was filtered off and dried. Yield 0.25 g (62%). White powder; mp 215-218°C (mp
1
223-224°C (EtOH-Et2O, 1:9) [14]). The H NMR and mass spectrometry data corresponded to that given in
[14].
2-(1-Hydroxyimino-2-oxo-2-phenylethyl)-6-methylpyrimidin-4(3H)-one (4). Compound 1 (1.0 g,
4.4 mmol) was dissolved in a minimal amount of AcOH (40-45 ml) at 80°C, and a saturated aqueous solution of
NaNO2 (0.9 g, 13.2 mmol) was added portionwise with stirring. The reaction mixture was left in a fume hood
until the major part of the solvent had evaporated. The residue was filtered off, washed on the filter with cold
water, dried, and recrystallized from EtOH. Yield 0.9 g (80%). White powder; mp > 215°C (decomp.). 1H NMR
spectrum, , ppm: 12.76 (1H, s, NОH); 12.44 (1H, s, NH); 7.84-7.56 (5H, m, H Ph); 6.26 (1H, s, H-5); 2.06
(3H, s, СH3). Mass spectrum, m/z (Irel, %): 257 [M]+ (34), 213 (16), 152 (95), 136 (31), 122 (10), 105 (100), 94
(9), 77 (76). Found, %: C 60.85; H 4.37; N 16.30. C13H11N3O3. Calculated, %: C 60.70; H 4.31; N 16.33.
2-(2-Hydroxyimino-2-phenylethyl)-6-methylpyrimidin-4(3H)-one (5). NH2OH·HCl (1.5 g, 22 mmol)
and pyridine (0.2 ml) were added to a saturated solution of compound 1 (0.5 g, 2.2 mmol) in refluxing EtOH
(45-50 ml) and refluxed for 8 h. The solvent was evaporated in vacuo, and the residue was treated with water
1489

(20 ml) and neutralized using AcOH. The precipitate formed was filtered off, dried in air and crystallized from
MeCN. Yield 0.25 g (46%). Colorless crystals; mp 235-236°C. 1H NMR spectrum, , ppm: 12.42 (1H, s, NH);
11.49 (1H, s, NОH); 7.72-7.36 (5H, m, H Ph); 6.00 (1H, s, H-5); 3.99 (2H, s, СH2); 2.02 (3H, s, СH3). Mass
spectrum, m/z (Irel, %): 243 [M]+ (33), 226 (18), 124 (100), 103 (13), 84 (15), 77 (15). Found, %: C 64.30;
H 5.55; N 17.30. C13H13N3O2. Calculated, %: C 64.19; H 5.39; N 17.27.
2-(1,2-Dihydroxyimino-2-phenylethyl)-6-methylpyrimidin-4(3H)-one (6). Compound 4 (0.5 g,
2.0 mmol) and KOH (2.3 g, 40 mmol) were dissolved in water (10 ml). NH2OH·HCl (1.4 g, 20 mmol) was
added, and the product was heated on a boiling water bath for 1.5 h. The reaction mixture was cooled and
neutralized with AcOH. The precipitate was filtered off, dried in air, and crystallized from MeCN. Yield 0.3 g
1
(57%). Colorless crystals; mp > 282°C (decomp.). H NMR spectrum, , ppm: 12.51 (1H, s, 1'-NОH); 12.19
(1H, s, NH); 11.56 (1H, s, 2'-NОH); 7.47-7.31 (5H, m, H Ph); 6.21 (1H, s, H-5); 2.07 (3H, s, СH3). Mass
spectrum, m/z (Irel, %): 272 [M]+ (18), 255 (47), 254 (100), 237 (47), 224 (23), 210 (28), 209 (25), 177 (20), 152
(18), 136 (23), 128 (15), 119 (20), 110 (22), 103 (42), 91 (16), 84 (37), 77 (64). Found, %: C 57.40; H 4.50;
N 20.50. C13H12N4O3. Calculated, %: C 57.35; H 4.44; N 20.58.
6-Methyl-2-(1-methyl-3-oxy-5-phenyl-1H-imidazol-4-yl)pyrimidin-4(3H)-one (7a). A mixture of
compound 4 (0.18 g, 0.7 mmol), paraformaldehyde (0.04 g, 1.4 mmol), and MeNH2·HCl (0.09 g, 1.4 mmol)
was refluxed in AcOH (5 ml) for 10 min. Solvent was evaporated in vacuo, and the residue was treated with an
equal volume of MeOH and allowed to crystallize. The crystals were filtered off and dried in air. Yield 0.10 g
1
(51%). Light-yellow crystals; mp > 250°C (decomp.). H NMR spectrum, , ppm: 15.12 (1H, br. s, NH); 8.90
(1H, s, H-2'); 7.56-7.46 (5H, m, H Ph); 6.01 (1H, s, H-5); 3.49 (3H, s, 1'-СH3); 2.07 (3H, s, 6-СH3). Mass
spectrum, m/z (Irel, %): 282 [M]+ (25), 266 (45), 265 (100), 184 (14), 118 (17), 84 (10), 77 (10). Found, %:
C 63.90; H 5.00; N 19.75. C15H14N4O2. Calculated, %: C 63.82; H 5.00; N 19.85.
2-[1-(2-Hydroxyethyl)-3-oxy-5-phenyl-1H-imidazol-4-yl]-6-methylpyrimidin-4(3H)-one (7b).
A
mixture of compound 4 (0.30 g, 1.17 mmol), paraformaldehyde (0.07 g, 2.40 mmol) and ethanolamine (0.15 ml,
2.40 mmol) was refluxed in AcOH (10 ml) for 15 min. Solvent was evaporated in vacuo, and the oily residue
was treated with an equal volume of CHCl3 and allowed to crystallize. The precipitate was filtered off, washed
with hot benzene, and crystallized from MeCN. Yield 0.10 g (30%). Light-yellow crystals; mp 228-230°C.
1H NMR spectrum, , ppm (J, Hz): 15.10 (1H, br. s, NH); 8.89 (1H, s, H-2'); 7.55-7.46 (5H, m, H Ph); 5.99 (1H,
s, H-5); 5.07 (1H, t, J = 6.0, ОH); 3.88 (2H, t, J = 5.4, NCH2CH2OH); 3.57 (2H, q, J = 5.4, NCH2CH2OH); 1.81
(3H, s, 6-СH3). Mass spectrum, m/z (Irel, %): 312 [M]+ (66), 296 (67), 295 (100), 279 (93), 268 (38), 253 (20),
252 (60), 251 (64), 182 (13), 170 (23), 128 (17), 116 (14), 104 (36), 84 (41), 77 (27). Found, %: C 61.67;
H 5.20; N 17.90. C16H16N4O3. Calculated, %: C 61.53; H 5.16; N 17.94.
2-[4-(4-Methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-oxy-5-phenyl-1H-imidazol-1-yl]acetic
Acid
(7c). A mixture of compound 4 (0.30 g, 1.17 mmol), paraformaldehyde (0.07 g, 2.40 mmol) and glycine (0.18 g,
2.40 mmol) was refluxed in AcOH (10 ml) for 15 min. Solvent was evaporated in vacuo, and the residue was
treated with an equal volume of MeOH and allowed to crystallize. The crystals were filtered off and dried in air.
1
Yield 0.20 g (55%). White powder; mp 238-242°C (decomp.). H NMR spectrum, , ppm: 15.02 (1H, br. s,
NH); 12.67 (1H, br. s, СO2H); 8.90 (1H, s, H-2); 7.54-7.38 (5H, m, H Ph); 6.03 (1H, s, H-5'); 4.64 (2H, s,
NCH2CO2H); 1.82 (3H, s, 6'-CH3). Mass spectrum, m/z (Irel, %): 326 [M]+ (18), 320 (10), 310 (51), 309 (74),
282 (15), 265 (14), 251 (16), 182 (11), 128 (51), 104 (12), 84 (15), 77 (10), 44 (100). Found, %: C 59.00;
H 4.35; N 17.22. C16H14N4O4. Calculated, %: C 58.89; H 4.32; N 17.17.
2-[4-(4-Methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-oxy-5-phenyl-1H-imidazol-1-yl]propionic
Acid
(7d). Obtained similarly to compound 7c from compound 4 (0.30 g, 1.17 mmol), paraformaldehyde (0.07 g,
1
2.40 mmol), and -alanine (0.20 g, 2.40 mmol). Yield 0.30 g (75%). White powder; mp 236-238°C. H NMR
spectrum, , ppm (J, Hz): 15.06 (1H, br. s, NH); 12.58 (1H, br. s, СO2H); 8.95 (1H, s, H-2); 7.56-7.47 (5H, m,
H Ph); 6.00 (1H, s, H-5'); 4.04 (2H, t, J = 6.9, NCH2CH2COOH); 2.68 (2H, t, J = 6.9, NCH2CH2COOH); 1.81
(3H, s, 6'-CH3). Mass spectrum, m/z (Irel, %): 340 [M]+ (16), 324 (18), 323 (22), 279 (26), 268 (100), 252 (32),
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251 (97), 224 (10), 208 (15), 185 (12), 168 (34), 136 (23), 128 (16), 116 (10), 110 (16), 104 (26), 89 (14), 84
(29), 77 (26). Found, %: C 60.10; H 4.77; N 16.50. C17H16N4O4. Calculated, %: C 60.00; H 4.74; N 16.46.
This work was carried out within the joint program "Ukraine National Academy of Sciences – Russian
Foundation for Basic Research" (No. 21-10).
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