Synthesis and Plant Growth Stimulating Action of 2-Amino-6-methylpyrimidine-4(3H)-thione Derivatives

Article abstract of DOI:10.1134/S1070363220020073

Abstract: A series of new pyrimidine derivatives, including those containing an azole or azine heterocycle linked through a sulfur atom or a thiomethylene group, was synthesized based on 2-amino-6-methylpyrimidine-4(3H)-thione. The synthesized compounds exhibited a pronounced stimulating effect on plants growth in the range of 43–96% compared to heteroauxin.

Full text of DOI:10.1134/S1070363220020073

ISSN 1070-3632, Russian Journal of General Chemistry, 2020, Vol. 90, No. 2, pp. 208–216. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Obshchei Khimii, 2020, Vol. 90, No. 2, pp. 225–235.
Synthesis and Plant Growth Stimulating Action
of 2-Amino-6-methylpyrimidine-4(3H)-thione Derivatives
a
a
a
a,b,
E. N. Hambardzumyan , A. S. Vorskanyan , L. V. Shahbazyan , and A. P. Yengoyan *
a
Research Center for Pesticide Synthesis and Plant Protection,
National Agrarian University of Armenia, Yerevan, 0009 Armenia
b
Russian-Armenian University, Yerevan, 0051 Armenia
*
e-mail: ayengoyan@mail.ru
Received July 22, 2019; revised July 27, 2019; accepted July 29, 2019
Abstract—Aseries of new pyrimidine derivatives, including those containing an azole or azine heterocycle linked
through a sulfur atom or a thiomethylene group, was synthesized based on 2-amino-6-methylpyrimidine-4(3H)-
thione. The synthesized compounds exhibited a pronounced stimulating effect on plants growth in the range of
4
3–96% compared to heteroauxin.
Keywords: 2-amino-6-methylpyrimidine-4(3H)-thione, heterocyclization, bi(tri)heterocyclic systems, azolyl(azinyl)-
thiopyrimidines, plant growth stimulating activity
DOI: 10.1134/S1070363220020073
Pyrimidine derivatives have a wide spectrum of
biological activity. The pyrimidine core is a part of the
natural compounds such as nucleic acids, vitamins, strong
poisons (tetrodotoxin), coenzymes, as well as a number
of synthetic drugs (barbiturates, sulfamides, antibiotics,
antitumor agents) [1, 2]. In recent years, new pyrimidine
derivatives with antitumor [3, 4], anti-inflammatory
pyrimidine derivatives, including compounds with a
combination of the initial pyrimidine ring with azines or
azoles, and to study their biological properties in terms
of searching for new chemical protective agents or plant
growth regulators.
Given the high reactivity and physiological activity of
heterocyclic compounds containing amino, mercapto and
alkylthio groups, we performed synthesis and function-
alization of 2-amino-6-methylpyrimidine-4(3H)-thione
[5, 6], antimicrobial [7–9], antifungal [10–12], antiviral
13], anticonvulsant [14], antioxidant [15, 16] and anti-
[
HIV [17, 18] activity have been synthesized. Some com-
pounds of this series have been proposed for the treatment
of cardiovascular diseases [19, 20], tuberculosis [21, 22],
and malaria [23, 24]. Potential corrosion inhibitors of steel
in an acidic medium were also found among compounds
of this series [25].
1
. The reaction of ethyl acetate and acetic acid with gua-
nidine nitrate and potassium n-butanolate in n-butanol
produces 2-amino-6-methylpyrimidin-4-ol. Chlorination
of the latter with phosphorus oxychloride gave rise to
the corresponding chloro derivative (Scheme 1). Further
reaction with thiourea in acetone and subsequent treat-
ment with potassium hydroxide through the intermediate
thiouronium salt resulted in the formation of the target
In agriculture, the most widely used herbicides are a
number of pyrimidines, which are divided into different
groups according to their chemical structure [26]. At the
same time, data on studies of compounds that include
the pyrimidine ring and azoles or azines in the molecule
are scarce, although a large number of chemical plant
protectors have been synthesized [26]. Such combination
of pharmacophore heterocycles can lead to the appear-
ance of two types of pesticidal activity at the same time.
2
-amino-6-methylpyrimidine-4(3H)-thione 1.
Compound 1 is easily alkylated, however, since this
compound can exist in six possible tautomeric forms
(A–F), depending on the position of the labile hydrogen
atoms, the alkylation can occur both at exocyclic sulfur
or nitrogen atoms and at the pyrimidine nitrogen atoms.
In the 13C NMR spectrum of compound 1 at
In this regard, the aim of this study was to develop
available and effective methods for the synthesis of new
181.3 ppm, a signal corresponding to the carbon atom of
the C=S double bond (structures D–F) is observed. In the
2
08

SYNTHESIS AND PLANT GROWTH STIMULATING ACTION
209
Scheme 1.
NH2
NH
O
O
n-C H OH
.
4 9
HNO3
NH2
+
+ n-C H OK
N
N
4
9
H N
H C
3
OC H5
2
2
H C
OH
3
S
NH2
NH2
NH2
NH
POCl3
N
N
N
N
NH2
NH
KOH
N
H N
NH
2
2
H C
Cl
H C
S
H C
3
S
3
3
1
NH
NH
NH2
NH2
HN
H C
N
N
NH
N
N
N
NH
SH
H C
3
SH
H C
3
SH
H C
3
S
3
Ⱥ
B
C
D
NH2
NH
NH
HN
H C
N
HN
H C
S
S
3
3
E
F
case of 4-methylthio derivative 2 obtained by methyla-
tion of 1 with dimethyl sulfate this absorption disappears
the SCH , N=CCH , N=CCH and COCH groups, and
2 3 2 3
only the proton of the NH group appears as two broad-
ened signals at 6.14 and 6.29 ppm. This spectral pattern
is apparently explained by the fact that the molecule has
an exclusively Z-configuration, which can be stabilized
due to the formation of dimers (G) or intramolecular
hydrogen bond (H).
(Scheme 2). So, in the spectra, signals of the S-methyl
group are observed at 2.43 and 11.3 ppm, respectively.
In this case, a two-proton broadened signal at 5.97 ppm,
corresponding to protons of the NH group, appears in
2
1
the H NMR spectrum. This data indicate that methyl
derivative 2 has the structure of tautomer C. Subsequent
reaction with tosyl chloride yielded an N-substitution
product 3 (Scheme 2).
The reaction of hydrazide 5 with CS in ethanol in
2
the presence of an equimolar amount of KOH resulted in
the formation of 2-[(2-amino-6-methylpyrimidin-4-yl)-
thio]methyl-1,3,4-oxadiazole-2(3H)thione 7 (Scheme 3).
Alkylation of compound 7 occurs at the sulfur atom of the
oxadiazole ring to form S-substituted derivatives 8a–8c.
Structure of the obtained compounds was confirmed by
Alkylation of compound 1 with monochloracetic acid
methyl ester resulted in an S-substituted product, namely
methyl 2-[(2-amino-6-methylpyrimidin-4-yl)thio]acetate
4
. Hydrazinolysis of the obtained acetate was carried out
using an aqueous solution of hydrazine hydrate in isopro-
pyl alcohol (Scheme 3). The reaction of hydrazide 5 with
acetylacetone furnished an acyclic condensation product
13
NMR data. Thus, in the C NMR spectrum of compound
, a signal corresponding to the carbon atom of the C=S
double bond is observed at 177.8 ppm, which disappears
7
6
instead of the expected heterocyclization product.
13
in the C NMR spectra of compounds 8a–8c.At the same
1
13
The molecule of compound 6 can exist in the form
time, in the H and C NMR spectra, signals correspond-
ing to S-alkyl groups are observed. Therefore, although
the 1,3,4-oxadiazole ring is in thioxo form in tautomer
1
13
of E- and Z-isomers. However, in the H and C NMR
spectra there is only one set of signals corresponding to
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020

210
HAMBARDZUMYAN et al.
Scheme 2.
O
O
S
NH2
HN
4-CH -C H SO Cl
3
6
4
2
N
N
N
N
CH3
H C
SCH3
H3C
SCH3
3
NH2
N
MS
3
D
2
N
H C
SH ClC
NH2
3
NH2
N
H2
CO
H
NNH
·H O
2
1
2
2
OCH3
N
N
N
H C
3
SCH COOCH
H C
3
SCH CONHNH2
2
2
3
4
5
Scheme 3.
CH3
O
O
O
NH2
N
N
N
CH3
H C
CH3
3
N
N
CH3 O
H
5
S
H
.
.
N
.
.
.
H C
S
CH3
O...
.
3
N
O
.
O
CS + KOH
C H OH
6
2
H
S
2
5
N
N
H C
N
3
NH2
N
NH2
N
O
CH3
G
N
N
RHlg
H C
3
O
O
H C
S
H C
S
3
S
3
SR
N
N
N
N
7
NH
N
N
CH3
ꢀ
ɚ–8c
O
...
S
H
O
H
5
ꢀ ꢀɋ+ (ɚ), CH CONH (b),
N
CH3 (c).
3
3
2
N
Cl
7
, the alkylation proceeds at the exocyclic sulfur atom to
cyclic systems with a combination of a pyrazole ring with
pyrimidine 10 or two pyrimidine rings 11 when reacted
with hydrazine hydrate, para-toluenesulfohydrazide
and thiourea (Scheme 4).
form S-substituted products.
The reaction of compound 1 with 3-chloropentane-2,4-
dione also proceeded at the sulfur atom, resulting in the
formation of 3-[(2-amino-6-methylpyrimidin-4-yl)thio]-
pentane-2,4-dione 9 (Scheme 4). According to H NMR
data, this compound exists mainly in enol form (17.30 ppm,
1
3
In the C NMR spectrum of compound 11, signal of
the carbon atom of the double C=S bond is observed at
196.9 ppm, which indicates the thionic structure of the
resulting pyrimidine ring.
1
0.8H, OH) and undergo heterocyclization to form hetero-
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SYNTHESIS AND PLANT GROWTH STIMULATING ACTION
211
Scheme 4.
O
O
NH2
N
NH2
N
R
H C
CH3
3
H C
O
S
CH3
CH3
3
Cl
RNHNH2
N
1
N
N
N
H C
H C
S
3
3
CH3
O
10a, 10b
9
NH2
S
NH2
NH2
H C
N
S
3
N
N
NH
CH3
H C
S
3
11
R = H (10a), 4-CH SO C H (10b).
3
2 6 4
In order to synthesize compounds with two azine
rings in the molecule, compound 1 was reacted with
,4-dichloro-6-methylpyrimidine and 2,4-dichloro-6-di-
compounds 1–15 at concentrations of 25 and 50 mg/L
on seed viability, germination and seedling growth was
studied. These data were compared with a similar effect
of heteroauxin solutions of the same concentrations. The
activity of the compounds ranged from 43–96% compared
to heteroauxin (Table 1). Biological screening data reflect
an interesting fact, when in some cases the stimulating
effect of solutions with a lower concentration turned out
to be higher than more concentrated solutions. Substances
exhibiting in the experiment activity above 80% (5, 6,
2
methylamino-1,3,5-triazine (Scheme 5). As a result, the
corresponding pyrimidinylthio- (12a) or triazinylthiopy-
rimidines (12b) were obtained. We previously showed
that in the first case, the reaction is carried out due at the
chlorine atom in the position 4 of the pyrimidine ring
27]. The reaction of the synthesized pyrimidines 12a
and 12c with hydrazine hydrate yielded the corresponding
hydrazides 13a, 13c (Scheme 5).
[
8
b, 8c, 10a, 12a, 13b, 14, 15) were selected for more
Some transformations of the obtained hydrazinopy-
rimidinylpyrimidine 13a were performed. Thus, the reac-
tion with acetylacetate in an acetic acid medium in the
presence of catalytic amounts of DMF provided a cyclic
product, pyrazolylpyrimidinylpyrimidine 14, whereas the
reaction with acetoacetic acid ethyl ester led to the forma-
tion of an acyclic condensation product 15 (Scheme 5).
in-depth study and further field testing using solutions
of synthesized compounds at concentrations <25 mg/L.
In conclusion, we developed effective methods for
the synthesis of 2-N- and 4-S-substituted derivatives
of 2-amino-6-methylpyrimidine-4(3H)-thione, includ-
ing compounds with a combination of pyrimidine ring
with various pharmacophore five-membered and six-
membered heterocycles. During preliminary biological
screening, the synthesized compounds showed a pro-
nounced stimulating effect on plant growth. The results
of the study indicate the promise of a further search for
new plant growth stimulants in the series of derivatives
studied.
The synthesized compounds were subjected to pre-
liminary laboratory vegetation tests to determine their
herbicidal, fungicidal and growth-regulating properties.
Almost all of the studied compounds showed a stimulating
effect on plant growth. The experiments were carried out
on the seeds and seedlings of common beans (Phaseolus
vulgaris L.). The effect of aqueous suspensions of
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212
HAMBARDZUMYAN et al.
Scheme 5.
Cl
X
NH2
NHNH
2
H C
3
NH2
O
O
N
N
NH NH
2
2
N
N
N
N
H C
3
CH3
N
N
N
CH3
NH2
N
N
H C
S
X
R
H C
S
R
3
3
N
N
N
1
2a, 12b
13a, 13b
H C
3
S
R
Cl
X
O
O
14
N
N
H C
OC H5
3
2
Cl
R
N
N
CH3
OC H5
NH2
NH2
N
HN
2
N
N
N
N
O
R
H C
S
H C
SH
3
3
1
15
X = CH, R = CH (ɚ); X = N, R = (CH ) N (b).
3
3 2
EXPERIMENTAL
2-Amino-4-methylthio-6-methylpyrimidine (2). To
a solution of 0.35 g (0.005 mol) of KOH in 2 mLof water
was added 0.7 g (0.005 mol) of compound 1. The mixture
was stirred for 5–10 min, and then 0.5 mL (0.005 mol) of
dimethyl sulfate was added under cooling with ice water.
The resulting mixture was stirred and left overnight.
The precipitate was filtered off, washed with a diluted
KOH solution, then with water. Yield 0.7 g (93.5%),
1
13
H and C NMR spectra were recorded at 30°С on
a Varian Mercury-300 NMR spectrometer (300 and
5 MHz, respectively) in DMSO-d –СCl (3 : 1) solutions
7
6
4
using a standard pulse sequence; TMS was used as the
internal standard. The reaction progress and the purity
of the obtained compounds were monitored by TLC on
Silufol UV-254 plates; an acetone–hexane mixture (2 : 1)
was used as an eluent. Elemental analysis was performed
on an Eurovector EA3000 CHNS analyzer. Melting points
were determined by capillary method without correction.
1
mp 155–156°С. Н NMR spectrum, δ, ppm: 2.17 s (3H,
CH -pyrimidine), 2.43 s (3H, SCH ), 5.97 br. s (2H,
3
3
1
3
NH ), 6.25 s (1H, CH-pyrimidine). С NMR spectrum,
2
δС, ppm: 11.3, 22.9, 105.7, 162.0, 164.5, 169.1. Found,
2-Amino-6-methylpyrimidine-4(3H)-thione (1). To
%: C 46.54; H 5.78; N 27.30. C H N S. Calculated, %:
6
9
3
a solution of 0.42 g (0.0055 mol) of thiourea in 30 mL
of acetone was added 0.1 mL of conc. HCl, then 7.2 g
C 46.43; H 5.84; N 27.07.
2
-(Tosylamino)-4-(methylthio)-6-methylpyrimi-
(0.0055 mol) of 2-amino-4-chloro-6-methylpyrimidine.
dine (3). A mixture of 0.8 g (0.005 mol) of compound 2
and 0.95 g (0.005 mol) of para-toluenesulfonyl chloride
in 2 mL of pyrimidine was stirred, then kept at room
temperature for 24 h. After treatment with diethyl ether
and water, the precipitate was filtered off and dried.
The mixture was boiled for 4–5 h, and then cooled. The
precipitate was filtered off and washed with diethyl ether.
The obtained thiuronium salt (12 g) was dissolved in
1
0 mL of water and neutralized with 2.4 g of Na CO
2 3
dissolved in 8–10 mL of water. The resulting precipitate
1
Yield 0.55 g (61.3%), mp 175–177°С. Н NMR spec-
trum, δ, ppm: 2.36 s (3H, CH -pyrimidine), 2.37 s (3H,
was filtered off, washed with water and dried. Yield 0.9 g
3
1
(
98%), mp > 280°С. Н NMR spectrum, δ, ppm: 2.07 s
CH ), 2.58 s (3H, SCH ), 6.66 s (1H, CH-pyrimidine),
3
3
(
6
3H, CH -pyrimidine), 6.29 s (1H, CH-pyrimidine),
7.12–7.63 m (4H, C H ), 12.5–13.5 br. s (1H, NH). 13С
3
6 4
13
.60 br. s (2H, NH ), 11.80 br. s (1H, NH). С NMR spec-
NMR spectrum, δ , ppm: 12.3, 17.8, 20.7, 106.2, 125.3,
2
С
trum, δ , ppm: 23.1, 114.0, 154.5, 163.2, 181.3. Found,
127.9, 138.5, 142.9, 153.7, 154.3, 179.2. Found, %: C
50.59; H 4.95; N 13.72. C H N O S . Calculated, %:
С
%
: C 42.44; H 4.89; N 29.55. C H N S. Calculated, %:
5 7 3
13 15
3
2 2
C 42.53; H 5.00; N 29.76.
C 50.47; H 4.89; N 13.58.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020

SYNTHESIS AND PLANT GROWTH STIMULATING ACTION
Table 1. Plant growth stimulating activity of compounds 2–15
213
c,
mg/L
c,
mg/L
Compound
Activity relative to heteroauxin, %
100.0
Compound
Activity relative to heteroauxin, %
Heteroauxin
25
9
25
63.7
5
0
100.0
54.3
–
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
25
50
–
2
3
4
5
6
7
25
10a
10b
12a
12b
13a
13b
13
82.2
74.0
58.8
63.7
83.0
–
5
0
25
77.4
68.9
76.3
61.3
82.6
67.3
67.4
95.9
65.1
43.3
79.1
65.5
95.0
85.1
86.3
83.4
5
0
25
5
0
25
61.4
64.4
63.1
43.3
70.8
83.7
84.7
56.2
90.5
–
5
0
25
5
0
25
5
0
8
8
8
a
b
c
25
5
0
25
15
5
0
25
5
0
Methyl 2-[(2-amino-6-methylpyrimidin-4-yl)thio]-
(0.007 mol) of 70% hydrazine hydrate was added under
cooling with ice water. The resulting mixture was stirred
for 0.5 h at room temperature and at 35°С for 1–2 h, then
5–8 mL of cold water was added. The precipitate was
filtered off and dried. Yield 0.85 g (85%), mp 200–202°С.
acetate (4). To a solution of 0.2 g (0.005 mol) of NaOH
in 3–4 mL of water was added 0.7 g (0.005 mol) of
compound 1. The mixture was stirred until the reagents
were completely dissolved, then 0.9 mL (0.005 mol) of
1
NaI·2H O and 0.55 g (0.005 mol) of methyl chloroacetate
Н NMR spectrum, δ, ppm: 2.17 s (3H, CH -pyrimidine),
2
3
were added. The resulting mixture was stirred at room
temperature, then at 35–40°С for 3 h and left overnight.
The next day, 4–5 mL of cold water was added, the
precipitate was filtered off and dried. Yield 0.9 g (85%),
3.66 s (2H, SCH ), 4.12 br. s (2H, NH–NH ), 6.31 s (1H,
2
2
CH-pyrimidine), 6.35 br. s (2H, NH ), 8.99 br. s (1H, NH).
2
1
3
С NMR spectrum, δ , ppm: 23.0, 30.0, 105.6, 162.2,
С
165.2, 167.1, 167.3. Found, %: C 39.33; H 5.16; N 32.67.
C H N OS. Calculated, %: C 39.42; H 5.20; N 32.84.
1
mp 108–110°С. Н NMR spectrum, δ, ppm: 2.19 s (3H,
7
11
5
CH -pyrimidine), 3.70 s (3H, OCH ), 3.91 s (2H, SCH ),
3
3
2
(Z)-2-[(2-Amino-6-methylpyrimidin-4-yl)thio]-
N'-(4-oxopentan-2-ylidene)acetohydrazide (6). A
mixture of 0.8 g (0.0038 mol) of compound 5, 0.65 mL
0.007 mol) of acetylacetone in 4–5 mL of dioxane was
6
.02 br. s (2H, NH ), 6.30 s (1H, CH-pyrimidine). 13С
2
NMR spectrum, δ , ppm: 22.9, 29.9, 51.7, 105.9, 162.0,
С
165.2, 166.5, 168.5. Found, %: C 44.91; H 5.12; N 19.51.
(
C H N O S. Calculated, %: C 45.06; H 5.20; N 19.70.
8
11
3
2
stirred at 60–70°С for 3–4 h.After removal of the solvent,
the residue was treated with water and filtered, washed
with a diluted HCl solution, then with water. Yield 0.6 g
2
-[(2-Amino-6-methylpyrimidin-4-yl)thio]ace-
tohydrazide (5). To a mixture of 1.07 g (0.005 mol)
of compound 4 in 5–6 mL of propan-2-ol, 0.5 mL
1
(60%), mp 275–276°С. Н NMR spectrum, δ, ppm:
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020

214
HAMBARDZUMYAN et al.
1
.79 s (3H, N=CCH ), 2.02 s (3H, COCH ), 2.17 s (3H,
2-Amino-4-{[({5-[(2-chloro-6-methylpyrimidin-
4-yl)thio]methyl}-1,3,4-oxadiazol-2-yl)methyl]
thio}-6-methylpyrimidine (8c). To a solution of 0.6 g
(0.002 mol) of the potassium salt of compound 7 obtained
by evaporation of a solution of 0.51 g (0.002 mol) of com-
pound 1 and 0.14 g (0.002 mol) of KOH in 5 mLof water,
0.37 g (0.002 mol) of 4-dichloro-6-methylpyrimidine 2
was added in 3 mL of DMF. The resulting mixture was
heated for 5–6 h at 40–50°С. DMF was removed at low
pressure. The residue was treated with water, filtered,
washed with a diluted NaOH solution, then with water and
3
3
CH -pyrimidine), 2.82 d and 2.85 d (2H, N=CCH , J =
3
2
1
6
8.9 Hz), 4.09 d and 4.24 d (2H, SCH , J = 15.4 Hz),
2
.01 br. s (2H, NH ), 6.14 s and 6.29 s (1H, NH), 6.32 s
2
1
3
(
1H, CH-pyrimidine). С NMR spectrum, δ , ppm:
С
1
1
5.7, 23.0, 25.9, 32.1, 51.9, 90.4, 105.9, 153.5, 162.0,
64.9, 165.0, 168.2. Found, %: C 48.92; H 5.88; N 23.94.
C H N O S. Calculated, %: C 48.80; H 5.80; N 23.71.
12
17
5
2
2
-Amino-4-[(2-thioxo-1,3,4-oxadiazol-5-yl)methyl]-
thio-6-methylpyrimidine (7). To a 84% solution of
.2 g (0.005 mol) KOH in 3–4 mLof absolute alcohol was
added 0.53 g (0.0025 mol) of compound 5, and then 0.4 g
0.005 mol) of СS . The resulting mixture was boiled
0
1
dried. Yield 0.45 g (60%), mp 148–50°С. Н NMR spec-
trum, δ, ppm: 2.20 s (3H, CH -pyrimidine), 2.45 s (3H,
(
3
2
CH -pyrimidine), 4.70 s (2H, SCH ), 6.20 br. s (2H, NH ),
for 5–6 h, then the solvent was removed and 5–6 mL of
water was added. The resulting solution was acidified
withAcOH. The precipitate was filtered off, washed with
3
2
2
6.35 s (1H, CH-pyrimidine), 7.37 s (1H, CH-pyrimidine).
Found, %: C 40.74; H 3.02; N 25.55. C H ClN OS .
13 12
7
2
1
Calculated, %: C 40.89; H 3.17; N 25.68.
water and dried. Yield 0.5 g (83%), mp 213–215°С. Н
NMR spectrum, δ, ppm: 2.20 s (3H, CH -pyrimidine),
3-[(2-Amino-6-methylpyrimidin-4-yl)thio]pen-
tane-2,4-dione (9). To a solution of 0.7 g (0.01 mol) of
84% KOH in 4 mL of water was added 1.4 g (0.01 mol)
of compound 1. The resulting mixture was stirred for
10–15 min, and then 1.47 g (0.011 mol) of 3-chloropen-
tane-2,4-dione was added in portions with cooling. The
mixture was stirred at room temperature for 1–2 h, and
then left overnight. Next, 2–3 mL of water was added
to the mixture, the precipitate was filtered off and dried.
3
3
6
.20–3.80 br. s (1H, NH + H O), 4.48 s (2H, SCH ),
2
2
3
1
.20 br. s (2H, NH ), 6.32 s (1H, CH-pyrimidine).
С
2
NMR spectrum, δ , ppm: 21.1, 23.0, 106.0, 160.2, 162.0,
С
165.0, 165.7, 177.8. Found, %: C 37.64; H 3.55; N 27.43.
C H N OS . Calculated, %: C 37.64; H 3.55; N 27.43.
8
9
5
2
General procedure for the synthesis of compounds
8a, 8b. To a solution of 0.14 g (0.002 mol) of KOH in
3 mL of water was added 0.5 g (0.002 mol) of compound
7. The mixture was stirred for 10–15 min, then 0.002 mol
1
Yield 1.8 g (78%), mp 180–181°С. Н NMR spectrum,
δ, ppm: 2.19 s (3H, CH -pyrimidine), 2.29 s (6H, СH ),
of dimethyl sulfate or chloroacetamide was added with
cooling. The resulting mixture was stirred for 0.5–1 h and
left overnight. The precipitate was filtered off and dried.
3
3
6
.12 br. s (2H, NH ), 6.13 s (1H, CH-pyrimidine), 17.30 s
2
1
3
(
0.8H, OH-enol). С NMR spectrum, δ , ppm: 23.2,
С
2
3.7, 98.7, 103.7, 162.4, 166.1, 168.9, 196.9. Found, %:
2-Amino-4-({[5-(methylthio)-1,3,4-oxadiazol-2-yl]-
C 50.27; H 5.60; N 17.71. C H N O S. Calculated, %:
1
0
13
3
2
methyl}thio)-6-methylpyrimidine (8a). Yield 0.4 g
C 50.19; H 5.48; N 17.56.
1
(
80%), mp 119–20°С. Н NMR spectrum, δ, ppm: 2.20 s
General procedure for the synthesis of compounds
(
3H, CH -pyrimidine), 2.69 s (3H, SCH ), 4.60 s (2H,
3
3
1
0a, 10b. A mixture of 0.48 g (0.002 mol) of compound
SCH ), 6.17 br. s (2H, NH ), 6.33 s (1H, CH-pyrimidine).
2
2
13
9, 0.2 mLof a 70% aqueous solution of hydrazine hydrate
or 0.4 g, 0.002 mol of para-toluenesulfohydrazide) and
С NMR spectrum, δ , ppm: 13.9, 20.9, 23.0, 105.9,
С
(
1
62.0, 164.2, 165.2, 165.7. Found, %: C 40.02; H 4.07;
3
2
mL of acetic acid was stirred at room temperature for
days.After removing the solvent, the residue was treated
N 26.13. C H N OS . Calculated, %: C 40.13; H 4.12;
9
11
5
2
N 26.00.
with water. The precipitate was filtered off and dried.
2
-[(5-{[(2-Amino-6-methylpyrimidin-4-yl)thio]-
2
-Amino-4-[(3,5-dimethyl-1H-pyrazol-4-yl)thio]-
methyl}-1,3,4-oxadiazol-2-yl)thio]acetamide (8b).
1
6-methylpyrimidine (10a). Yield 0.45 g (98%), mp
Yield 0.5 g (83%), mp 179–181°С. Н NMR spectrum, δ,
1
ppm: 2.20 s (3H, CH -pyrimidine), 3.95 s (2H, SCH CO),
123–125°С. Н NMR spectrum, δ, ppm: 2.09 s and
3
2
4
.59 s (2H, SCH ), 6.22 br. s (2H, NH ), 6.34 s (1H,
2.16 s (6H, СH3-pyrazole), 2.16 s (3H, CH3-pyrimidine),
2
2
CH-pyrimidine), 7.09 s and 7.56 s (2H, NH -amide).
5.67s(1H, CH-pyrimidine), 6.02br. s(2H, NH ), 11.76br. s
2
2
13
13
С NMR spectrum, δ , ppm: 20.9, 23.0, 105.9, 162.1,
(1H, NH). С NMR spectrum, δ , ppm: 10.3, 20.4, 23.2,
С
С
1
3
63.6, 164.4, 165.2, 165.7, 167.3. Found, %: C 38.31; H
.78; N 26.75. C H N O S . Calculated, %: C 38.45;
99.0, 103.0, 146.9, 162.0, 165.6, 171.1, 171.6. Found, %:
C 51.04; H 5.57; N 29.76. C H N S. Calculated, %: C
10
12
6
2
2
10 13
5
H 3.87; N 26.90.
51.04; H 5.57; N 29.76.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020

SYNTHESIS AND PLANT GROWTH STIMULATING ACTION
215
2
-Amino-4-[(3,5-dimethyl-1-tosyl-1H-pyrazol-4-
General procedure for the synthesis of compounds
13a, 13b. To a solution of 1.35 g (0.005 mol) of compound
12 in 5 mL of dioxane was added 1 mL (0.014 mol) of a
70% aqueous solution of hydrazine hydrate. The mixture
was kept at room temperature for 24 h. After removal of
dioxane, 8–10 mL of water was added to the residue. The
precipitate was filtered off and dried.
yl)thio]-6-methylpyrimidine (10b). Yield 0.6 g (77%),
mp 129–130°С. Н NMR spectrum, δ, ppm: 2.08 s and
.45 s (6H, СH -pyrazole), 2.20 s (3H, CH -pyrimidine),
.55 s (3H, CH C H ), 5.77 s (1H, CH-pyrimidine),
.20 br. s (2H, NH ), 7.40–7.89 m (4H, C H ). Found, %:
C 52.33; H 4.85; N 17.77. C H N O S . Calculated, %:
1
2
2
6
3
3
3
6
4
2
6
4
17
19
5
2 2
C 52.42; H 4.92; N 17.98.
2
-Amino-4-[(2-hydrazinyl-6-methylpyrimidin-
5
-[(2-Amino-6-methylpyrimidin-4-yl)thio]-4,6-
4-yl)thio]-6-methylpyrimidine (13a). Yield 1.0 g (73%),
mp 185–187°С. Н NMR spectrum, δ, ppm: 2.25 s (3H,
1
dimethylpyrimidine-2(1H)-thione (11). To a solution
of 0.3 g (0.004 mol) of thiourea in 4–5 mL of absolute
ethanol was added 0.48 g (0.002 mol) of compound 9,
and then 0.7 mL of conc. HCl. The resulting mixture
was boiled for 2 h, then left overnight. After removal of
the solvent, the residue was dissolved in water, neutral-
CH -pyrimidine), 2.28 s (3H, CH -pyrimidine), 4.01 br. s
3
3
(2H, NH–NH ), 6.30 br. s (2H, NH ), 6.64 s (1H, CH-
2
2
pyrimidine), 6.68 s (1H, CH-pyrimidine), 7.90 br. s (1H,
NH). 13С NMR spectrum, δ , ppm: 23.3, 23.4, 109.3,
С
109,5, 162.5, 163.3, 164.6, 165.3, 166.6, 166.9. Found,
%: C 45.49; H 4.87; N 37.05. C H N S. Calculated, %:
ized with NaHCO and filtered off. Yield 0.44 g (60%),
mp 175–176°С. Н NMR spectrum, δ, ppm: 2.19 s (3H,
3
10 13
7
1
C 45.61; H 4.98; N 37.24.
CH -pyrimidine), 2.27 s (6H, СH -pyrimidine), 6.08 br. s
3
3
2-Amino-4-[(2-hydrazinyl-6-N,N-dimethylamino-
(
2H, NH ), 6.13 s (1H, CH-pyrimidine), 17.28 br. s (1H,
2
1,3,5-triazin-4-yl)thio]-6-methylpyrimidine (13b).
NH). 13С NMR spectrum, δ , ppm: 23.2, 23.7, 98.7,
1
С
Yield 1.0 g (69%), mp 204–206°С. Н NMR spectrum,
1
03.6, 162.4, 166.1, 168.9, 196.9. Found, %: C 47.29;
δ, ppm: 2.25 s (3H, CH -pyrimidine), 3.13 s and 3.18 s
3
H 4.69; N 25.07. C H N S . Calculated, %: C 47.29;
11
13
5
2
[6H, N(CH ) ], 2.90–3.20 br. s [NHNH + N(CH ) +
3
2
2
3 2
H 4.69; N 25.07.
H O], 6.20 br. s (2H, NH ), 7.32 s (1H, CH-pyrimidine),
2
2
General procedure for the synthesis of compounds
2a, 12b. To a mixture of 1.8 g (0.01 mol) of the potas-
8.38 br. s (1H, NH). Found, %: C 40.80; H 5.04; N 42.75.
C10H15N9S. Calculated, %: C 40.94; H 5.15; N 42.97.
1
sium salt of compound 1 in 5 mLof DMF, 1.6 g (0.01 mol)
of 2,4-dichloro-6-methylpyrimidine (or 1.9 g 0.01 mol of
2-Amino-4-{[2-(3,5-dimethyl-1H-pyrazol-1-yl)-
6-methylpyrimidin-4-yl]thio}-6-methylpyrimidine
(14).Amixture of 0.53 g (0.0025 mol) of compound 13a,
1 mL of acetylacetone and 1–2 drops of DMF in 5 mL of
glacial acetic acid was stirred for 10–15 min and kept at
room temperature for 24 h. After removing the solvent,
the residue was treated with water; the precipitate was
filtered off, washed with diluted HCl solution and dried.
2,4-dichloro-6-dimethylamino-1,3,5-triazine) was added
with cooling. The mixture was stirred at room tempera-
ture for 0.5–1 h, and then heated for 5–6 h at 40–50°С.
After cooling, the residue was treated with cold water;
the precipitate was filtered off and dried.
2
-Amino-4-[(2-chloro-6-methylpyrimidin-4-yl)-
1
Yield 0.65 g (81%), mp 209–210°С. Н NMR spectrum,
thio]-6-methylpyrimidine (12a). Yield 1.4 g (67%),
1
δ, ppm: 2.24 s and 2.41 s (6H, СH -pyrazole), 2.54 s and
mp 158–160°С. Н NMR spectrum, δ, ppm: 2.24 s (3H,
3
2
7
.55 s (6H, CH -pyrimidine), 5.98 s (1H, CH-pyrazole),
3
CH -pyrimidine), 2.49 s (3H, CH -pyrimidine), 6.50 br. s
3
3
.22 s (1H, CH-pyrimidine), 7.36 br. s (2H, NH ), 7.54 s
(
2H, NH ), 6.59 s (1H, CH-pyrimidine), 7.77 s (1H,
2
2
13
(1H, CH-pyrimidine). С NMR spectrum, δ , ppm: 13.2,
CH-pyrimidine). Found, %: C 44.95; H 3.81; N 26.38.
Calculated, %: C 44.86; H 3.76; N 26.16.
С
1
1
5
5
4.4, 21.1, 23.5, 109.2, 109.4, 117.1, 141.8, 149.4, 155.7,
59.1, 162.7, 164.0, 165.4, 168.1. Found, %: C 55.03; H
.23; N 29.95. C H N S. Calculated, %: C 55.03; H
2-Amino-4-[(2-N,N-dimethylamino-6-chloro-1,3,5-
1
5
17
7
triazin-4-yl)thio]-6-methylpyrimidine (12b). Yield
.23; N 29.95.
1
2
.5 g (84%), mp 198–200°С. Н NMR spectrum, δ, ppm:
Ethyl 3-(2-{4-[(2-amino-6-methylpyrimidin-4-yl)-
2
.28 s (3H, CH -pyrimidine), 3.13 s and 3.19 s [6H,
3
N(CH ) ], 6.33 br. s (2H, NH ), 7.05 s (1H, CH-pyrim-
thio]-6-methylpyrimidin-2-yl}hydrazono)butanoate
(15). A mixture of 0.4 g (0.0015 mol) of compound 13a,
0.75 mL of acetoacetic acid ester and 1–2 drops of DMF
in 0.8 mL of acetic acid was kept at room temperature
for 24 h. After removal of the solvent, the residue was
3
2
2
idine). 1 С NMR spectrum, δ , ppm: 23.3, 35.9, 36.0,
3
С
111.7, 162.1, 162.5, 162.8, 166.9, 167.7, 178.7. Found,
%
: C 40.30; H 4.10; N 32.72. C H ClN S. Calculated,
10 12 7
%: C 40.34; H 4.06; N 32.93.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020

216
HAMBARDZUMYAN et al.
treated with water; the precipitate was filtered off, washed
12. Wang, S.C., Gao, J.-G., Zhang, S., Liu, S., and Jiang, L.,
Phosphorus, Sulfur, Silicon, Relat. Elem., 2018, vol. 193,
p. 245.
with diluted HCl solution and dried. Yield 0.4 g (71%),
1
mp 120–121°С. Н NMR spectrum, δ, ppm: 1.28 t (3H,
https://doi.org/10.1080/10426507.2017.1395439
OCH CH , J = 7.1 Hz), 2.00 s (3H, N=CCH ), 2.25 s
2
3
3
1
3. Holy, A., Votruba, I., Masojìdkova, M., Andrei, G.,
Snoeck, R., Naesens, L., De Clercq, E., and Balzarini, J.,
J. Med. Chem., 2002, vol. 45, p. 1918.
and 2.34 s (6H, CH -pyrimidine), 3.32 s (2H, COCH ),
3
2
4
6
.13 q (2H, OCH CH , J = 7.1 Hz), 6.33 br. s (2H, NH ),
2 3 2
.83 s and 6.86 s (2H, CH-pyrimidine), 9.62 br. s (1H,
https://doi.org/10.1021/jm011095y
13
NH). С NMR spectrum, δ , ppm: 13.8, 15.7, 20.5, 23.3,
С
1
4. Dalkara, S., Karakurt, A., Curr. Top. Med. Chem., 2012,
vol. 12, p. 1033. doi 10.2174/156802612800229215
5. Abu-Hashem, A.A., Youssef, M.M., and Hussein, H.A.R.,
J. Chin. Chem. Soc., 2011, vol. 58, p. 41.
4
1
3.8, 59.8, 109.4, 111.3, 144.8, 159.4, 162.4, 164.6, 166.8,
66.9, 169.1, 171.0. Found, %: C 51.19; H 5.64; N 26.11.
1
C H N O S. Calculated, %: C 51.19; H 5.64; N 26.11.
16
21
7
2
https://doi.org/10.1002/jccs.201190056
6. Abu-Hashem, A.A., El-Shehry, M.F., and Badria, F.A.,
Act. Pharm., 2010, vol. 60, p. 311. doi 10.2478/v10007-
CONFLICT OF INTEREST
1
No conflict of interest was declared by the authors.
0
10-0027-6
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 2 2020