Isomerization/recyclization of some 5-ethoxycarbonyl-pyrimidines

Article abstract of DOI:10.1002/jhet.5570420413

This communication reports on the investigation of a new recyclization conversion of a pyrimidine ring, which can be referred to as C-C recyclization. In this reaction the nucleophile cleaves the pyrimidine ring at the N(3)-C(4) bond, and following rotation around the single C(5)-C(6) bond the new cyclization takes place. This type of recyclization has general applicability, and takes place upon alkali treatment of substituted 4-methyl-5-ethoxycarbonyl- and 4-amino-5-ethoxycarbonyl-pyrimidines (1) which are transformed respectively to 4-hydroxy-5-acetyl- and 4-hydroxy-5-carbamoylpyrimidines (2). The obtained pyrimidyl-ketones can be readily converted to their hydrazones 7-12.

Full text of DOI:10.1002/jhet.5570420413

May-Jun 2005
557
Isomerization/Recyclization of some 5-Ethoxycarbonyl-pyrimidines
R. S. Vardanyan and V. J. Hruby
Department of Chemistry, University of Arizona,
1306 E. University Blvd., Tucson, Arizona 85721
G. G. Danagulyan and A. D. Mkrtchyan
Institute of Organic Chemistry National Academy of Sciences,
167A Z.Kanakerttsi St., 375091 Yerevan, Republic of Armenia
Received November 1, 2004
This communication reports on the investigation of a new recyclization conversion of a pyrimidine ring,
which can be referred to as C-C recyclization. In this reaction the nucleophile cleaves the pyrimidine ring at
the N(3)-C(4) bond, and following rotation around the single C(5)-C(6) bond the new cyclization takes
place. This type of recyclization has general applicability, and takes place upon alkali treatment of substi-
tuted 4-methyl-5-ethoxycarbonyl- and 4-amino-5-ethoxycarbonyl-pyrimidines (1) which are transformed
respectively to 4-hydroxy-5-acetyl- and 4-hydroxy-5-carbamoylpyrimidines (2). The obtained pyrimidyl-
ketones can be readily converted to their hydrazones 7-12.
J. Heterocyclic Chem., 42, 557 (2005).
Reactions accompanied by opening of a heterocyclic
rearrangement [3-6], are mechanistically close to the Dimroth
rearrangement, and have been studied in some detail recently
[7-13]. The principle distinction of these transformations
from the Dimroth rearrangement is the substitution of the
endocyclic nitrogen atom of a pyrimidine ring in the α-posi-
tion by an exocyclic carbon atom (such reactions can be figu-
ratively called N-C recyclizations) (Scheme B).
This communication is devoted to an investigation of an
additional recyclization conversion of a pyrimidine ring,
which is based on an atom substitution proceeding in the
heterocycle, and which can be referred to as C-C recycliza-
tion (Scheme C).
Vardanyan et al. made the first observation of this type
of rearrangement in 1982 [14].
Here we show that that this type of recyclization has
general applicability, and takes place upon alkali treatment
of substituted 4-methyl-5-ethoxycarbonyl- and 4-amino-5-
ethoxycarbonyl-pyrimidines (1) which are transformed
ring and subsequent ring closure comprise a signifi-
cant reaction in the chemistry of pyrimidines. Such
transformations which may be viewed as "recycliza-
tions", generally proceed under the action of nucle-
ophilic agents and can be accompanied either by intro-
duction of a nucleophilic fragment into the newly
formed cycle, or simply may aid in the ring opening/
ring closure process. In the latter case, formation of a
new reaction product is the result of the isomeriza-
tion/recyclization. Among isomerization/recyclization
reactions of pyrimidines, the most studied are the
Dimroth rearrangements [1], proceeding at the
expense of a nitrogen exocyclic atom introduction
(being in the α-position of pyrimidine) into a newly
formed pyrimidine ring (Scheme A). Actually, in this
rearrangement substitution of a ring nitrogen atom by
an exocyclic nitrogen atom takes place.
Scheme A. (N-N recyclizations)
Transformations of pyrimidine derivatives into pyridine
derivatives [2], generally referred to as the Kost-Sagitullin
respectively to 4-hydroxy-5-acetyl- and 4-hydroxy-5-car-
bamoylpyrimidines (2) as shown on the next page.
Scheme B. N-C recyclizations

558
R. S. Vardanyan, V. J. Hruby, O. G. Danagulyan, and A. D. Mkrtchyan
Vol. 42
Thus, isomerization of 5-ethoxycarbonyl-pyrimidines
respectively to 4-hydroxy-5-acetyl- and 4-hydroxy-5-car-
bamoylpyrimidines, and particularly of keto-pyrimidines
has enough general character and could be considered as a
convenient method for the synthesis of new starting mate-
rials for medicinal chemistry.
Of principle importance is that as distinct from the
above-mentioned isomerizational recyclizations of pyrim-
idines - this reaction (Scheme C) does not require addi-
tional activation by quaternization of a pyrimidine nitro-
gen atom. Probably, the latter is connected with the avail-
ability in position 5 of the ring of an electron-acceptor
ethoxycarbonyl group that increases the electron defi-
ciency of a pyrimidine nucleus, and hence provides the
opportunity for a nucleophilic attack and cleavage of the
cyclic compound.
Scheme C. (C-C recyclizations)
Synthesis of the 2-substituted-4-amino-5-ethoxycar-
bonyl-pyrimidines (1a-c) was carried out by heterocycliza-
tion of ethoxymethyleneacetoacetic acid ethyl ester with
urea, thiourea or guanidine [14,15].
a) R = CH , X = OH; b) R = CH , X = SH; c) R = CH , X = NH
2
3
3
3
d) R = NH , X = OH; e) R = NH , X = SH;
f) R = NH , X = Bn.
2
2
2
In this reaction the nucleophile cleaves the pyrimidine
ring at the N(3)-C(4) bond, and following rotation around
the single C(5)-C(6) bond, the new cyclization takes
place. As a result, the carbon atom of the ester group is
included in the newly formed pyrimidine ring, whereas
the pyrimidine carbon atom C-4 appears outside the hete-
rocycle ring, and leads to obtaining a thermodynamically
more advantageous structure, the 5-carbamoylpyrimidine
derivative.
Synthesis of 2-substituted-4-amino-5-ethoxycarbonyl-
pyrimidines (1e) and (1f) was carried out by the reaction of
a thiourea or phenylacetic amidine with the ethyl ester of
ethoxymethylenecyanoacetate.
With the aim of clarifying the possibility of the nucle-
ophilic attack at position 6 of a pyrimidine ring and obtain-
ing the corresponding 5-formyl derivative (4), we have
synthesized one more model - 2-hydroxy-4-methyl-5-
acetylpyrimidine (3). However, we failed to obtain the
transformation product which would result from attack on
atom C-6, namely, the 2-hydroxy-4,6-dimethyl-5-
formylpyrimidine; only the initial pyrimidine was isolated.
The corresponding 2-hydroxyderivatives 1d and 3
were synthesized by heterocyclization of cyanoacetic
ester and acetylacetone ureidomethylene derivatives 5
and 6 in ethanol in the presence of sodium ethoxide. The

May-Jun 2005
Isomerization/Recyclization of some 5-Ethoxycarbonyl-pyrimidines
559
vent. The sample temperature was 303 K. Mass-spectra were reg-
istered on a MK-1321 spectrometer with direct sample introduc-
tion into the ion source and an ionization energy of 70 eV. TLC
latter are obtained by the interaction of urea and ethyl
orthoformate, and correspondingly with cyanoacetic
ester and acetylacetone.
5. R = CN, X = OEt.
6. R =MeCO, X = M
Taking into account the interesting biological behavior
of hydrazones and their metal complexes as antitumor [17-
19], antiviral [20] and antibacterial and antifungal com-
pounds [21,22], keto-pyrimidines - 5-acetyluracil (2a) and
2-hydroxy-4-methyl-5-acetylpyrimidine (3) were trans-
formed to their hydrazones (7-12) by reactions with substi-
tuted hydrazines and isonicotinic hydrazide.
was performed on Silufol UV-254 platelets, developed by iodine
vapors and Erlich reagent.
2-Substituted-4-Methyl-5-ethoxycarbonyl-pyrimidines (1a-c),
were prepared according to methods described in the literature
[14,15].
2-Mercapto-4-methyl-5-ethoxycarbonyl-pyrimidine (1b).
A mixture of 7.6 g (0.1 mol) of thiourea and sodium alcoholate
(prepared from 3.45 g of sodium and 130 mL of absolute ethyl
alcohol) was heated until complete dissolution of thiourea, and
18.6 g (0.1 mol) of ethyl ethoxymethyleneacetoacetic ester was
added dropwise. The solution was heated for 8 h, alcohol was
evaporated in vacuo, the residue was dissolved in a minimal
quantity of water and acidified with acetic acid (pH ≈ 6). The pre-
cipitate formed was collected by filtration, washed with water,
alcohol and acetone. Obtained was 17 g (86%) of 2-mercapto-4-
The hydrazones have been submitted for biological testings.
EXPERIMENTAL
NMR spectra were obtained on a Varian «Mercury 300» with a
resonance frequency of 300.077 MHz for the hydrogen nucleus
13
and 75.46 MHz for the C nucleus. DMSO-d was used as sol-
6
I
X = OH, Me.
R = Aryl, Het, COHet.
R = H, Allyl.

560
R. S. Vardanyan, V. J. Hruby, O. G. Danagulyan, and A. D. Mkrtchyan
Vol. 42
methyl-5-ethoxycarbonyl-pyrimidine (1b), mp 188-189°, R 0.75
g of sodium and 150 mL of absolute alcohol. The mixture was
boiled for 1 h and the solvent was evaporated in vacuo. The
residue was dissolved in water and acidified with 20 mL of acetic
acid. The precipitate that formed was collected filtration, washed
with acetone and dried to afford 29.8 g (78%) of 2-hydroxy-4-
f
(acetone-toluene, 3:1). Corresponded to the authentic sample
1
obtained by the mentioned route [14]. H nmr: δ ppm (J, Hz):
1.37 (3H, t, 7,1, CH ), 2.57 (3H, s, 4-CH ), 4.27 (2H, q, 7.1,
3
3
CH O), 3.1-3.3 (1H, br s, SH), 8.54 (1H, s, 6-H).
2
Anal. Calcd. for C H N O S: C 48.47; H 5.08; N 14.13; S
16,18. Found: C 48.29; H 4.76; N 13.89; S 16,07.
methyl-5-acetylpyrimidine (3) as yellow crystals, mp 211-212°,
8
10 2 2
1
R 0.64 (ethanol). H nmr: δ ppm (J, Hz): 2.44 (3H, s, 4-CH ),
f
3
2.55 (3H, s, CH CO), 5.20-5.50 (1H, s, OH), 8.78 (1H, s, 6-H).
3
2-Hydroxy-4-amino-5-ethoxycarbonyl-pyrimidine (1d).
Anal. Calcd. for C H N O : C 55.26; H 5.30; N 18.41. Found:
7
8 2 2
To a solution of sodium ethoxide prepared from 3.7 g (0.16
mol) of sodium and 200 mL of absolute ethanol, 27.5 g (0.15
mol) of ethyl-ureidomethylenecyanacetate (5) was added and the
mixture was boiled for 2 h. The formed precipitate was collected
by filtration, dissolved in 800 mL of water and acidified with
acetic acid (12 mL). The precipitated crystals were collected by
filtration, washed with acetone, and dried. There was obtained 23
g (84%) of 2-hydroxy-4-amino-5-ethoxycarbonyl-pyrimidine
C 55.00; H 5.03; N 18.23.
Ethyl Ureidomethylenecyanacetate (5).
A mixture of 28.25 g (26.6 mL, 0.25 mol) of cyanoacetic acid
ethyl ester, 59.2 g (66.4 mL, 0.4 mol) of ethyl ortho-formate and
15 g (0.25 mol) of urea was boiled with stirring under reflux for
10 h. The mixture was then cooled, the precipitate collected by
filtration, washed with acetone and dried. The yield of ethyl urei-
_
_
1
(1d), mp 274-276 , lit. 278-282 [15]. H nmr: δ ppm (J, Hz):
domethylenecyanoacetate (5) was 28.8 g (63%), mp 215-216°, R
f
1
1.30 (3H, t, CH ), 4.23 (2H, q, CH O), 7.6 (1H, br s, NH), 7.74
0.58 (CCl -C H -CH COOH, 1:2:1). H nmr: δ ppm ( J, Hz):
3
2
4
6
6
3
(1H, br s, NH), 8.18 (1H, s, 6-H), 11.23 (1H, br s, OH).
1.35 (3H, d, J=7.2, CH ), 4.25 (2H, q, J=7.2, CH O), 7.65 (1H, ,
3
2
Anal. Calcd. for C H N O : C 45.90; H 4.95; N 22.94. Found:
C 45.59; H 4.71; N 22.55.
NH), 7.83 (1H,br s, NH), 8.19 (1H, s, CH), 11.5 (1H, br s,
7
9 3 3
13
NH(OH). C nmr; δ ppm: 14.027 (CH ), 30.642 (CH ), 59.003
3
3
(CH ), 103.996 (=C), 149.514 (CH=), 152.645 (NC(0)-N),
165.450 (COO), 197.994 (CO).
2
2-Mercapto-4-amino-5-ethoxycarbonyl-pyrimidine (1e).
To a solution of sodium ethoxide, prepared from 0.8 g (0.035
mol) of sodium and 35 mL of absolute alcohol, was added 2.3 g
(0.03 mol) of thiourea and the mixture was heated until complete
dissolution. To the stirred solution was added dropwise a solution
of 5.1 g (0.03 mol) of ethoxymethylene-cyanoacetic acid ethyl
ether in 10 mL of ethanol. The reaction mixture was boiled for 8
h, and alcohol was evaporated in vacuo. The dry residue was dis-
solved in water and acidified with 3.5 mL of acetic acid. The pre-
cipitate formed was collected by filtration, washed with water,
alcohol, and ether, and dried to obtain 5.2 g (87%) of pyrimidine
Anal. Calcd. for C H N O : C 45.90; H 4.95; N 22.94. Found:
C 45.69; H 4.76; N 22.59.
6
6 2 3
Ureidomethyleneacetone (6).
A mixture of 30 g (0.5 mol) of urea, 81.4 g (91 mL, 0.55 mol)
of orthoformate and 3 mL (50 g, 0.51 mol) of acetylacetone was
boiled with stirring under reflux for 8 h. The mixture was then
cooled and the precipitate collected by filtration. The crystals
were washed with acetone and dried. Obtained was 47.5 g (56%)
of ureidomethyleneacetylacetone (6), mp 201-203°, R 0.67
f
o
1
1
(1e), mp 260-262 [16]. H nmr: δ ppm (J, Hz): 1.35 (3H, t, 7.1,
(CCl -C H -CH COOH, 1:2:1) H nmr: δ ppm (J, Hz): 2.32
4
6
6
3
CH ), 3.05-3.50 (1H, br s, SH), 4.25 (2H, q, 7.1, CH O), 7.85
(3H, s, CH ), 2.38 (3H, s, CH ), 6.91-7.12 (1H, br s, NH), 7.50-
3
2
3
3
(1H, br s, NH), 8.04(1H, s, 6-H), 8.61 (1H, s, NH).
7.73 (1H, br s, NH), 8.35 (1H, d, CH), 11.31 (1H, d, NH).
Anal. Calcd. for C H N O S: C 45.20; H 4.55; N 21.09; S
16,09. Found: C 45.39; H 4.56; N 21.39; S 16,36.
7
9 3 2
Rearrangement of 2-Hydroxy-4-methyl-5-ethoxycarbonyl-
pyrimidine (1a) to 5-Acetyluracil (2a).
2-Benzyl-4-amino-5-ethoxycarbonyl-pyrimidine (1f).
To a solution prepared from 10 g (0.178 mol) of potassium
hydroxide and 90 mL of water was added 4.5 g (0.025 mol) of
2-hydroxy-4-methyl-5-ethoxycarbonyl-pyrimidine (1a) [16]
and the mixture was boiled for 1 h. The mixture was then acid-
ified with 25 mL of conc. hydrochloric acid and the solution
was evaporated to dryness. To the residue was added 20 mL of
water. The crystals formed were collected by filtration to
To a solution of sodium ethoxide, prepared from 0.8 g (0.035
mol) of sodium and 40 mL of absolute ethanol, was added 6 g
(0.035 mol) of phenylacetamidine hydrochloride. The mixture
was stirred for a short time and cooled to 0°. The formed precipi-
tate was rapidly filtered. The filtrate was mixed with a hot solu-
tion of 5.8 g (0.034 mol) of ethoxy-methylenecyanoacetic acid
ethyl ester in 10 mL of ethanol. The mixture was boiled with stir-
ring for 5 h. After partial removal of the alcohol, the residue was
collected by filtration and washed with acetone and ethylacetate
afford 1.9 g (49%) of 5-acetyluracil (2a), mp 290-291 °C, R
0.59 (acetone-toluene, 3:1). mp 294-295° [15]. H nmr: δ
f
1
ppm (J, Hz): 2.85 (3H, s, CH ) 8.03 (1H, s, 6-H), 10.81-11.80
3
to afford 4.2 g (48%) of pyrimidine 1f, mp 148-150° , R 0.7
(2H, br s, OH); ms: m/z (I , %): 154 (85), 139 (100), 96
(18.6), 69 (31.4), 43 (29.50), 28 (40).
f
rel
1
(ethanol). H nmr: δ ppm (J, Hz): 1.38 (3H, t, J = 7.1, CH ), 3.95
3
(2G, s, CH ), 4.33 (2H, q, J = 7.1, CH ), 7.13-7.31 (5H, m,
Anal. Calcd. for C H N O : C 46.76; H 3.92; N 18.18.Found:
2
2
6
6 2 3
C H ), 7.55 (2H, br s, NH ), 8.64 (1H, s, 6-H).
C 46.49; H 3.75; N 18.31.
6
5
2
Anal. Calcd. for C H N O : C 65.35; H 5.88; N 16.33.
Found: C 65.19; H 4.86; N 15.98.
14 15
3 2
Rearrangement of 2-Mercapto-4-methyl-5-ethoxycarbonyl-
pyrimidine (1b) to 2-Mercapto-4-hydroxy-5-acetylpyrimidine
(2b).
2-Hydroxy-4-methyl-5-acetylpyrimidine (3).
To a hot solution of 42.5 g (0.25 mol) of ureidomethyle-
neacetylacetone (6) in 350 mL of absolute ethyl alcohol was
added dropwise a solution of sodium ethoxide prepared from 6.5
To 100 g of 10% water solution of potassium hydroxide was
added 4.95 g (0.025 mol) of 2-mercapto-4-methyl-5-ethoxycar-
bonyl-pyrimidine (1b). The mixture was boiled for 10 min, acid-

May-Jun 2005
Isomerization/Recyclization of some 5-Ethoxycarbonyl-pyrimidines
561
ified with 25 mL of conc. hydrochloric acid and the water was
removed under reduced pressure to the volume of 20 mL. The
mixture was then cooled, the crystals that precipitated were col-
lected by filtration and dried in the air. The yield of 2-mercapto-
4-hydroxy-5-acetylpyrimidine (2b), was 3.3 g (77%); mp 320-
Interaction of 2-Hydroxy-4-methyl-5-acetylpyrimidine (3) with
Alkali.
Similar to the previous experiments, 1.52 g (0.01 mol) of 2-
hydroxy-4-methyl-5-acetyl-pyrimidine (3) was boiled in a solu-
tion prepared from 5 g (0.089 mol) of potassium hydroxide and
45 mL of water for 1 h. Then the mixture was acidified with 32%
hydrochloric acid and the solution was evaporated to 20 mL and
extracted with ether. The initial substance remained without
changes. Chromatographic examination did not reveal formation
of a new product.
322°, corresponded to the authentic sample obtained by the other
1
route [14]. H nmr: δ ppm (J, Hz): 2.55 (3H, s, COCH ), 3.05-
3
3.17 (1H, br s, SH), 3.4-4.8 (1H, br s, OH), 8.65 (1H, s, 6-H).
Anal. Calcd. for C H N O S: C 42.34; H 3.55; N 16.46; S
6
6 2 2
18,84.Found: C 42.09; H 3.75; N 18.31; S 18,46.
Rearrangement of 2-Amino-4-methyl-5-ethoxycarbonyl-pyrimi-
dine (1c) into 2-Amino-4-hydroxy-5-acetylpyrimidine (2c).
2,4-Dihydroxy-5-{1-[(2-benzyl-4-methylpyrimidin-6-yl)-hydra-
zono]ethyl}pyrimidine (7).
To water-ethanol (1:1) potassium hydroxide solution, obtained
by dissolution of 1 g of potassium hydroxide 20 mL of solvent
was added 1.8 g (0.1 mol) of 2-amino-4-methyl-5-ethoxycar-
bonyl-pyrimidine (1c). The mixture was boiled for 30 min, the
alcohol was evaporated in vacuo, and 1.2 mL of acetic ester was
added. The precipitated residue was collected by filtration,
washed with water and dried to afford 1.2 g (80%) of product
(2c), mp 301-302°, corresponded to the authentic sample
obtained by the other route [14].
A mixture of 1.54 g (0.01 mol) of 2,4-dihydroxy-5-
acetylpyrimidine (2a) and 2.15 g (0.01 mol) of 2-benzyl-4-
methyl-6-hydrazinopyrimidine [23] in 20 mL (0.35 mol) of
absolute ethanol was boiled during 12 h. The mixture was cooled,
the residue was collected by filtration, washed with alcohol, ace-
tone and dried to afford 2.5 g (71%) of product (7), mp 228-230°,
1
R 0.43 (CCl -acetone, 1:1). H nmr: δ ppm (J, Hz): 2.18 (3H, s,
f
4
CH CN), 2.30 (3H, s, 4-CH ), 3.94 (2H, s, CH ), 6.80 (1H, s, 5-
3
3
2
H), 7.15-7.30 (5H, m, C H ), 7.49 (1H, d, J= 6.0 Hz, 6-H), 9.95
6
5
(1H, s, 4-OH), 11.04 (1H, d, J=6.0 br s, 1-NH), 11.11 (1H, s,
Rearrangement of 2-Substituted-4-amino-5-ethoxycarbonyl-
pyrimidines (1d and 1e) into 2-Substituted-4-hydroxy-5-car-
bamoylpyrimidines (2d and 2e).
NH); ms: m/z (I , %): 350 (6.3), 335 (6.6), 334 (23), 333 (100),
rel
332 (63.6), 306 (6), 292 (6.7), 291 (8), 182 (22), 171 (17), 117
(8.9), 116 (8.9), 91 (39.8).
5-Ethoxycarbonyl-pyrimidine (1d) or (1e) (0.025 mol) of
was boiled in 100 g of 10% potassium hydroxide solution. Ten
minutes later, after the crystals had dissolved, the solution was
acidified with 25 mL of conc. hydrochloric acid after which
the water was completely evaporated off. The residue was
poured into 20 mL of cold water and stirred for several min-
utes. The precipitate was collected by filtration and dried in
the air. There was obtained, correspondingly, 2.3 g (59.4%) of
Anal. Calcd. for C
Found C 61.43; H 4.85; N 24.27.
H N O : C 61.70; H 5.18; N 23.99.
18 18 6 2
2,4-Dihydroxy-5-{1-[(2-benzyl-4-methyl-5-allylpyrimidin-6-
yl)hydrazono]ethyl}-pyrimidine (8).
To a solution of 0.25 g (0.9 mmol) of 2-benzyl-4-methyl-5-
allyl-6-hydrazinopyrimidine [22] in 20 mL of ethanol was added
0.14 g (0.9 mmol) of 5-acetyluracil (2a) and 2-3 drops of
hydrochloric acid, and the mixture was boiled for 5 h. The yellow
crystals were collected by filtration, washed with acetone and
ether, and recrystallized from alcohol to give 0.19 g (54%) of
5-carbamoyluracil (2d), mp > 300°, R 0.54 (acetone-toluene,
f
2:1) and 2.25 g (52.6%) of 2-mercapto-4-hydroxy-5-carba-
moylpyrimidine (2e), mp > 300°, R 0.48 (acetone-toluene,
f
1
2:1); H nmr: δ ppm of compound (2d): 7.53 (1H, br s, NH),
1
product (8), mp 267-270°, R 0.61 (ethanol). H nmr: δ ppm (J,
f
8.03 (1H, s, 6-H), 8.38 (1H, br s, NH), 10.7–11.2 [2H, s, OH
Hz): 2.3 (3H, s, CH -C=N), 2.45 (3H, s, 4-CH ), 3.43 (2H, d,
3
3
(NH)]. Anal. Calc. for C H N O : N 27.09. Found: N 27.34.
5
5
3
3
CH -CH=CH ), 3.95 (2H, s, CH ), 4.98 (1H, d, J = 10.0,
2 2 2
1
H nmr: δ ppm of compound (2e): 2.9-3.5 (1H, br s, SH), 8.0
CH=CH ), 5.08 (1H, d, J = 16.8, CH=CH ), 5.81 (1H, ddm, J =
2
2
(1H, s, 6-H), 8.02 (1H, s, NH), 8.53 (1H, s, NH), 11.8-13.2
5.5, J = 10.0, J = 16.8), 7.15-7.25 (5H, m, C H ), 7.57 (1H, d, J =
5.8, 6-H), 8.45 (1H, s, 2-OH), 11.04-11.1 (1H, br s, N).
Anal. Calcd. for C N O : C 64.60; H 5.68; N 21.52.
6
5
(1H, br s, OH); ms: m/z (I , %): 171 (100), 127 (42), 113
rel
(12), 95 (14), 85 (20), 71 (10), 70 (21), 69 (28), 68 (28), 67
(14), 53 (13), 52 (11), 44 (18).
H
21 22
6 2
Found: C 64.34; H 5.35; N 21.31.
Anal. Calc. for C H N O S: N 24.55; S 18.73. Found: N
5
5 3 2
2-Hydroxy-4-methyl-5-{1-[(2,4-dinitrophenyl)hydrazono]-
ethyl}pyrimidine (9).
24.78; S 18.89.
2-Benzyl-4-hydroxy-5-carbamoylpyrimidine (2f).
A mixture of 1.5 g (0.01 mol) of 2-hydroxy-4-methyl-5-
acetylpyrimidine (3), 1.94 g (0.01 mol) of 2,4-dinitrophenylhy-
drazine and 2-3 drops of hydrochloric acid was heated for 8 h in
30 mL of absolute ethanol. The precipitated crystals were col-
lected by filtration and washed with alcohol to give 2.65 g (81%)
of 2-hydroxy-4-methyl-5-{1-[(2,4-dinitrophenyl)hydrazono]-
2-Benzyl-4-amino-5-ethoxycarbonyl-pyrimidine (1f) (0.5 g, 2
mmol) was boiled in 60 mL of 5% solution of potassium hydrox-
ide for 1 h. The mixture was then acidified with 10% solution of
hydrochloric acid until the pH 6 and the water was evaporated off
to a volume of 20 mL. The mixture was cooled with stirring for
several minutes, the precipitate was collected by filtration and
dried in the air to give 0.28 g (62.4%) of compound (2f), mp 240-
ethyl}pyrimidine (9), mp 192-193°, R 0.66 (CCl -acetone, 1:1);
H nmr: δ ppm (J, Hz): 2.43 (3H, c, 4-CH ), 2.58 (3H, c,
f
4
1
3
1
241°, R 0.54 (i-PrOH-ammonia-water 7:0.5:1). H nmr: δ ppm
CH C=N), 7.95 (1H, d, 6`-H), 8.35 (1H, d, 5`-H), 8.45 (1H, br s,
f
3
of compound (2f): 3.95 (2H, s, CH ), 7.1-7.35 (5H, m, C H ),
7.43 (1H, br s, NH), 7.71 (1H, br s, NG), 8.64 (1H, s, 6-H), 10.6
– 12.4 (1H, br s, OH).
NH), 8.95 (1H, c, 6-CH), 11.13 (1H, s, 3`H), 11,31-12,27 (1H, br
s, OH).
2
6 5
Anal. Calcd. for C
H N O : C 46.99; H 3.64; N 25.29.
13 12 6 5
Anal. Calcd. for C H N O : N 18.33. Found N 18.57.
Found: C 46.64; H 3.45; N 25.58.
12 11
3 2

562
R. S. Vardanyan, V. J. Hruby, O. G. Danagulyan, and A. D. Mkrtchyan
Vol. 42
REFERENCES AND NOTES
2-Hydroxy-4-methyl-5-{1-[(4,6-dimethylpyrimidin-2-yl)-hydra-
zono]ethyl}pyrimidine (10).
[1] D. J. Brown, Mechanisms of Molecular Migrations, John
Wiley and Sons, New York, NY, Vol. I, 1968, pp 209.
[2] R. S. Sagitullin and A. N. Kost, Zh. Org. Khim. (Russ.), 16,
658 (1980).
[3] R. S. Sagitullin, T. V. Melnikova and A. N. Kost, Khimiya
Geterotsiklicheskikh Soedineniy (Russ.), 1436 (1974); Chem. Abstr., 82,
43311 (1975).
[4] A. N. Kost, R. S. Sagitullin and G. G. Danagulyan, Khimiya
Geterotsiklicheskikh Soedineniy, 558 (1977); Chem. Abstr., 87, 68284
(1977).
[5] R. S. Sagitullin, A. N. Kost and G. G. Danagulyan,
Tetrahedron Letters, 1435 (1978).
[6] A. N. Kost, R. S. Sagitullin and G. G. Danagulyan, Khimiya
Geterotsiklicheskikh Soedineniy, 1400 (1978); Chem. Abstr., 90, 72137
(1979).
[7] G. G. Danagulyan, A. P. Boyakhchyan and A. A. Safaryan,
Chemistry of Heterocyclic Compounds, 31, 1370 (1995).
[8] G. G. Danagulyan and L. G. Sahakyan, Chemistry of
Heterocyclic Compounds, 35, 1251 (1999).
To a solution of 1 g (7.2 mmol) of 2-hydrazino-4,6-
dimethylpyrimidine [17] in 40 mL of ethanol, was added 1.1 g
(7.2 mmol) of 2-hydroxy-4-methyl-5-acetylpyrimidine (3) and 3-
4 mL of hydrochloric acid, and the mixture was heated under
reflux for 10-12 h. On completion the mixture was cooled and the
precipitate of the unreacted acetylpyrimidine was filtered off.
After removal of the solvent from the alcoholic solution the solid
residue was recrystallized from the mixture benzene-acetone
(1:1). Obtained was 1.4 g (71%) of product (10) as white crystals,
_
1
mp 226-228 , Rf 0.58 (CCl -acetone, 1:1). H nmr δ ppm (J,
4
1
Hz):2.43(3H, s, 4-CH ), 2.46 (3H, s, CH ), 2.55 (6H, s, 4 - and
6 -CH ), 7.11 (1H, s, 5 -H), 8.98 (1H, s, 6-H).
3
3
1
1
3
Anal. Calcd. for C
H N O: C 57.34; H 5.92; N 30.86.
13 16 6
Found: C 57.61; H 5.86; N 30.59.
2-Hydroxy-4-methyl-5-{1-[(2-benzyl-4-methyl-5-allylpyrim-
idin-6-yl)-hydrazono]ethyl} pyrimidine (11).
A mixture of 1.52 g (0.01 mol) of 5-acetylpyrimidine (3) and
2.55 g (0.01 mol) of 2-benzyl-4-methyl-5-allyl-6-hydrazinopy-
rimidine [23] was boiled in 20 mL of absolute ethanol for 15 h.
On completion the mixture was cooled and the precipitated crys-
[9] G. G. Danagulyan, L. G. Sahakyan, A. R. Katritzky and S. N.
Denisenko, Chemistry of Heterocyclic Compounds, 35, 1572 (1999).
[10] G. G. Danagulyan, L. G. Sahakyan, A. R. Katritzky and S. N.
Denisenko, Heterocycles, 53, 419 (2000).
[11] G. G. Danagulyan and L. G. Sahakyan, Chemistry of
Heterocyclic Compounds, 36, 613 (2000).
[12] G. G. Danagulyan, L. G. Sahakyan and H. A. Panosyan,
Chemistry of Heterocyclic Compounds, 37, 3512 (2001).
[13] G. G. Danagulyan, F. S. Kinoyan and D. A. Tadevosyan,
Chemistry of Heterocyclic Compounds, 39, 303 (2003).
[14] R. S. Vardanyan, Zh. V. Ghazaryan and S. A. Vardanyan,
Khimiya Geterotsiklicheskikh Soedineniy (Russ.), 1558 (1982); Chem.
Abstr., 98, 72051 (1983).
[15] W. Bergmann and T. B. Johnson, Ber., 66, 1492 (1933).
[16] T. L. V. Ulbricht and Ch. C. Price, J. Org. Chem., 21, 567
(1956).
tals were filtered off, washed with alcohol and acetone and dried.
_
Obtained was 2.49 g (64%) of product (11), mp 243-245 , R 0.7
f
1
(ethanol). H nmr: δ, ppm (J, Hz): 2.07 (3H, d, J = 2.2), 2.19 (3H,
s, CH ), 2.37 (3H, s, CH ), 3.55-3.70 (2H, m, CH -CH=CH ),
3
3
2
2
3.97 and 4.01 (2H, dd, J = 13.8, CH -CH=), 4.90-4.97 (2H, m,
2
=CH ), 5.81 (1H, br s, NH), 5.89 (1H, m, CH=), 6.18 (1H, s,
2
NH), 7.13-7.33 (5H, m, C H ), 9.23 (1H, d, 6-H).
6
5
Anal. Calcd. for C
H N O: C 68.02; H 6.23; N 21.63.
22 24 6
Found: C 68.31; H 6.53; N 21.47.
Isonicotinic Acid [1-(2-Hydroxy-4-methylpyrimidin-5-yl)-eth-
ylidene]hydrazide (12).
[17] F. Kratz, A. Warnecke, K. Scheuermann, C. Stockmar, J.
Schwab, P. Lazar, P. Drückes, N. Esser, J. Drevs, D. Rognan, C. Bissantz,
C. Hinderling, G. Folkers, I. Fichtner and C. Unger, J. Med. Chem., 45,
5523 (2002).
[18] D. R. Richardson and P. V. Bernhardt, J. Biol. Inorg. Chem., 4,
266 (1999).
[19] M. C. Rodriuez-Arguelles, M. Belicchi errari, F. Bisceglie, C.
Pelizzi, G. Pelosi, S. Pinelli and M. Sassi, J. Inorg. Biochem., 98, 313
(2004).
[20] B. Modzelewska-Banachiewicz and T. Kaminska, Eur. J.
Med. Chem., 36, 93 (2001).
[21] F. H. Havaldar and S. K. J. Mishra, Indian J. Heteterocycl.
Chem., 13, 165 (2003).
[22] S. G. Kucukguzel, A. Mazi, F. Sahin, S. Ozturk and J. Stables,
Eur. J. Med. Chem., 38, 1005 (2003).
[23] G. G. Danagulyan, L. G. Sahakyan, P. B. Terent'ev and M. G.
Zalinyan, Armenian Chem. J., 44, 448 (1991); Chem. Abstr., 117, 191807
(1992).
To a solution of 1.52 g (0.01 mol) of 2-hydroxy-4-methyl-5-
acetylpyrimidine (3) was added 1.37 g (0.01 mol) of pyridyl-4-
carboxylic acid hydrazide, 25 mL of ethyl alcohol and 3-4 drops
of conc. hydrochloric acid, and the mixture was heated for 2 h.
The residue was collected by filtration, washed with ether and
acetone, and dried to obtain 2.1 g (77%) of hydrazone (12), mp
1
270-271°, R 0.62 (ethanol). H nmr: δ ppm (J, Hz): 2.13 (3H, s,
f
4-CH ), 2.23 (3H, s, CH -C=N), 6.0 (1H, br s, NH), 6.57 (1H, d,
3
3
1
1
J = 6.0 Hz, NH), 7.75 (2H, d, J = 6,8 Hz, 2 -H 6 -H), 8.65 (2H, d,
1
1
J =6,8 Hz , 3 -H and 5 -H), 9.47 (1H, d, J = 6.0 Hz, NH); ms: m/z
(I , %): 271 (11.4), 270 (7.7), 257 (6), 256 (39.3), 230 (11.6),
rel
228 (31), 227 (7.5), 151 (69.4), 138 (8), 137 (100), 122 (10.4),
106 (56.7), 96 (42), 94 (15), 79 (10), 78 (45), 60 (17).
Anal. Calcd. for C H N O : C 57.56; H 4.83; N 25.82.
13 13
5 2
Found: C 57.31; H 4.50; N 26.07.