Aryl ethers of 4-[(2-hydroxyethyl)sulfanyl]pyrimidine derivatives: Pathways of synthesis and fungicidal activity of their salt forms

Article abstract of DOI:10.1134/S1070363216060098

2-Amino-4-[(2-aryloxyethyl)sulfanyl]-6-methylpyrimidines were obtained by S-alkylation of 2-amino-6-methylpyrimidin-4(3H)-thione with 2-aryloxyethyl chlorides. Since 2-amino-4-[(2-chloroethyl)sulfanyl]-6-methylpyrimidine is prone to in situ intramolecular cyclization it cannot be used in Claisen reaction. The bromination of the target compounds provided 5-bromo derivatives; some of their hydrochlorides exhibited fungicidal activity.

Full text of DOI:10.1134/S1070363216060098

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 6, pp. 1274–1281. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © A.V. Erkin, I.V. Klaptyuk, V.V. Gurzhii, O.S. Yuzikhin, V.I. Krutikov, 2016, published in Zhurnal Obshchei Khimii, 2016, Vol. 86,
No. 6, pp. 944–951.
Aryl Ethers of 4-[(2-Hydroxyethyl)sulfanyl]pyrimidine
Derivatives: Pathways of Synthesis and Fungicidal Activity
of Their Salt Forms
A. V. Erkina, I. V. Klaptyukb, V. V. Gurzhiic, O. S. Yuzikhind, and V. I. Krutikova
a St. Petersburg State Institute of Technology (Technical University), Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: kruerk@yandex.ru
b St. Petersburg University of State Fire Service at the Emergency Situations Ministry of Russian Federation,
St. Petersburg, Russia
c St. Petersburg State University, St. Petersburg, Russia
d Kirov St. Petersburg State Forest Technical University, St. Petersburg, Russia
Received December 17, 2015
Abstract—2-Amino-4-[(2-aryloxyethyl)sulfanyl]-6-methylpyrimidines were obtained by S-alkylation of 2-amino-6-
methylpyrimidin-4(3H)-thione with 2-aryloxyethyl chlorides. Since 2-amino-4-[(2-chloroethyl)sulfanyl]-6-
methylpyrimidine is prone to in situ intramolecular cyclization it cannot be used in Claisen reaction. The
bromination of the target compounds provided 5-bromo derivatives; some of their hydrochlorides exhibited
fungicidal activity.
Keywords: 2-amino-6-methylpyrimidin-4(3H)-thione, S-alkylation, 2-aryloxyethyl ethers, bromination, fungicidal
activity
DOI: 10.1134/S1070363216060098
Azoles are ranked as most important among the
medicines for the treatment of candidiasis, an infectious
disease caused by pathogenic strains of Candida yeasts
[1]. New generation antifungals includes 2-(2,4-di-
fluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1Н-1,2,4-
triazol-1-yl)butane-2-ol which under the name Vorico-
nazole has passed phase III of clinical trials [2].
Hydrochlorides of benzyl ethers of 2-amino-6-
methylpyrimidin-4(3H)-thione are capable of 100% in
vitro inhibiting the growth of Candida albicans cells
(strain 15) in low (≤0.093 mmol/L) concentrations [3].
The introduction of halogen atoms into the aromatic
moiety of compound 1 caused a decrease in the
inhibition concentrations of above species.
Here we aimed to synthesize analogs of benzyl
ethers of 1 such as 2-amino-4-[(2-arylhydroxyethyl)sulfanyl]-
6-methylpyrimidines 2a–2d and 2-amino-4-[(2-aryl-
oxyethyl)sulfanyl]-5-bromo-6-methylpyrimidines 3a–
3d, including those containing halogen atoms in aro-
matic ring, and to study the antifungal activity of their
hydrochlorides.
Thioethers 2a–2d were prepared by S-alkylation of
2-amino-6-methylpyrimidin-4(3H)-thione 4 [4] with 2-
Scheme 1.
S
Me
Br
Me
Ar
Cl
O
HN
H2N
N
N
NBS
5а−5d
O
O
Me
N
H2N
H2N
N
S
N
S
Ar
Ar
3а−3d
2а−2d
4
Ar = Ph (a), 2-FC6H4 (b), 4-ClC6H4 (c), 2,4-Cl2C6H3 (d).
1274

ARYL ETHERS OF 4-[(2-HYDROXYETHYL)SULFANYL]PYRIMIDINE DERIVATIVES
1275
Scheme 2.
HO
SOCl , Py
2
Cl
Ar
OH
5а−5d
ArOH
O
6а−6d
Scheme 3.
Me
N
Me
N
S
Cl−
SOCl2, Py
N+
N
N
Me
OH
Cl
H2N
S
H2N
N
S
NH2
7
8
B
HO
H2O
Cl
4
Me
S
Cl−
S
+
H2O
Cl−
Me
HN
+
N
OH
H2N
N
H2N
N
9
C
HCl
7
aryloxyethyl chlorides 5a–5d in DMF in the presence
of potassium carbonate at 100°C. Thioethers 3a–3d
were obtained through bromination of compounds 2a–
2d with N-bromosuccinimide (NBS) in boiling
chloroform (Scheme 1).
and bending (1640–1605 cm–1) vibrations of amino
group, C=N (1570–1525 cm–1) and C=C (1470–
1445 cm–1) vibrations, as well as asymmetrical (1265–
1230 cm–1) and symmetric (1060–1010 cm–1)
vibrations of C–O–CAr bond (Table 2).
Compounds 5a–5d were synthesized via O-alkyla-
tion of the corresponding phenols with 2-chloroethanol
in aqueous medium in the presence of an equimolar
amount of sodium hydroxide at 80°C, followed by
chlorination of the intermediate 2-aryloxyethanols 6a–
6d with thionyl chloride in chloroform in the presence
of pyridine (Scheme 2).
An attempt to obtain compounds 2a–2d by Claisen
reaction failed. Exchange chlorination of 2-amino-4-
[(2-hydroxyethyl)sulfanyl]-6-methylpyrimidine 7 with
thionyl chloride in chloroform in the presence of
pyridine provided chromatographically pure product
(Rf 0.26, mp 181ºC) (eluent A). Aqueous solution of
the latter showed positive test for the presence of
1
The structure and the composition of the prepared
compounds were confirmed by NMR and IR spectro-
chloride ion when treating with silver nitrate. The H
NMR spectrum of compound A contained no signals
of OH group in the range of 4–6 ppm. The signal of
amino group appeared as two broadened singlets about
7.8 and 8.7 ppm. In the 13C NMR spectrum the signals
of methyl group and heterocyclic moiety were shifted
upfield [ΔδС 4.8 (Me), 7.8–11 ppm (C2,6)] and
downfield [ΔδС 9.9 ppm (С4)] relative to the signals of
identical atoms in compound 7. According to the facts
1
scopy and by elemental analysis (Tables 1, 2). The H
NMR spectra of thioethers 2a–2d and 3a–3d contained
the signals of methyl (2.1–2.3 ppm) and NH2 groups
(6.5–6.8 ppm), as well as the triplets of CH2CH2 unit
(3.4–4.3 ppm) and multiplets of aromatic protons (6.9–
7.5 ppm). In the IR spectra the following absorption
bands were attributed to the stretching (3492–3443 cm–1)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 6 2016

1276
ERKIN et al.
Table 1. Yields, melting points, Rf values, and elemental analysis data of 2-amino-4-[(2-aryloxyethyl)sulfanyl]-6-
methylpyrimidines (2a–2d) and 2-amino-4-[(2-aryloxyethyl)sulfanyl]-5-bromo-6-methylpyrimidines (3a–3d)
Comp. Yield,а
Rf
(A)
Found, %
H
Calculated, %
H
mp, ºС
Formula
no.
%
C
N
C
N
2а
2b
2c
2d
3а
3b
3c
3d
62
55
57
51
41
44
44
43
135
127
128
141
146
163
151
152
0.60
0.57
0.65
0.63
0.74
0.63
0.69
0.71
59.46
55.67
52.37
46.85
46.02
43.33
41.26
37.85
5.69
5.13
4.51
3.65
3.84
3.72
3.41
2.76
15.81
14.82
14.11
12.53
12.27
11.57
10.86
10.33
С13H15N3OS
59.75
55.90
52.79
47.28
45.89
43.59
41.67
5.79
5.05
4.77
3.97
4.15
3.66
3.50
2.96
16.08
15.04
14.21
12.72
12.35
11.73
11.21
10.27
С13H14FN3OS
С13H14ClN3OS
С13H13Cl2N3OS
С13H14BrN3OS
С13H13BrFN3OS
С13H13BrClN3OS
С13H12BrCl2N3OS 38.16
a After recrystallization.
1
Table 2. Н NMR and IR spectral data of 2-amino-4-[(2-aryloxyethyl)sulfanyl]-6-methylpyrimidines (2a–2d) and 2-amino-4-
[(2-aryloxyethyl)sulfanyl]-5-bromo-6-methylpyrimidines (3a–3d)
δ, ppmа
C5H
NH2
ν, cm–1
Comp.
no.
b
c
Me
CH2
CH2
Ar
NH2
C=N, C=C
C–O–CAr
2а
2b
2c
2d
3а
3b
3c
3d
2.14 s
2.14 s
2.14 s
2.15 s
2.31 s
2.30 s
2.30 s
2.31 s
3.48 t 4.17 t 6.43 s 6.57 s 6.92–7.27 m
3.50 t 4.25 t 6.42 s 6.56 s 6.92–7.37 m
3.46 t 4.17 t 6.41 s 6.55 s 6.96, 6.98 d, 7.30, 7.32 d 3461 s, 1637 s 1560 s, 1467 s 1241 s, 1035 s
3.50 t 4.27 t 6.40 s 6.50 s 7.19, 7.21 d, 7.33–7.50 m 3443 s, 1631 s 1556 s, 1463 s 1265 s, 1016 s
3475 s, 1633 s 1569 s, 1463 s 1232 s, 1029 s
3465 s, 1629 s 1570 s, 1470 s 1261 s, 1018 s
3.49 t 4.19 t
3.51 t 4.26 t
3.48 t 4.19 t
3.52 t 4.28 t
–
–
–
–
6.74 s 6.92–7.29 m
6.76 s 6.92–7.12 m
6.77 s 6.97, 6.99 d, 7.31, 7.33 d 3477 s, 1633 s 1527 s, 1463 s 1262 s, 1012 s
6.75 s 7.19, 7.21 d, 7.34–7.37 m 3492 s, 1606 s 1535 s, 1446 s 1242 s, 1057 s
3468 s, 1633 s 1527 s, 1463 s 1238 s, 1026 s
3471 s, 1629 s 1527 s, 1467 s 1255 s, 1012 s
a
b
c
Integral intensity of the signals corresponded to the protons number. Stretching and bending vibrations. Asymmetric and symmetric
vibrations.
mentioned above, compound A can be identified [5] as
7-amino-8-methyl-4-thia-6-azabicyclo[3.2.2]nona-5,7,8-
triene-1-azonium chloride B (Scheme 3).
regarded as an alternative product of intramolecular
cyclization of compound 8. According to quantum-
chemical calculations, the charges at the ring hetero
atoms of compound 8 are of close values [q N1/N3
–0.323/–0.347 (MNDO), –0.237/–0.252 (AM1) and
–0.174/–0.190 (PM3)].
When recrystallizing compound A from aceto-
nitrile–95% ethanol mixture (2 : 1), neither melting
point nor character of melting were not changed;
another behavior was observed when using other
solvents. Thus, the treatment of A with 98% methanol
resulted in the formation of pyrimidylthioethanol
hydrochloride 9, whose structure was confirmed by X-
ray diffraction data (Table 3). This unexpected result
indicated that compound A was prone to hydrolysis
with the residual water contained in organic solvents
which did not form azeotropes with it. In this case the
presented 1H and 13C NMR spectral data may
correspond to hydrochloride 9. If this did occur, then
along with bicyclic compound B 5-amino-7-methyl-
2,3-dihydro[3,2-c]pyrimidinium chloride C should be
It is remarkable that a similar feature, the absence
1
of the signal of OH group, was observed in the H
NMR spectrum of compound 9 obtained by passing
dry hydrogen chloride through a suspension of
pyrimidylthioethanol 7 in benzene. This feature can be
ex-plained only by assuming the identical character of
hydrogen bonding both in the crystal (Fig. 1) and in
DMSO-d6 solution.
The analysis of compound A by HPLC-MS using
aqueous organic eluent allowed to identify several
products of its degradation. Among them chloride 8
was detected as monoprotonated molecule [M + H]+
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 6 2016

ARYL ETHERS OF 4-[(2-HYDROXYETHYL)SULFANYL]PYRIMIDINE DERIVATIVES
1277
(m/z 204, Irel 5%); the most intensive peak (m/z 186) in
the spectrum belonged to molecular ion [M + H]+ of
pyrimidylthioethanol 7. The presence of isotopic peak
[M + 2 + H]+ (m/z 206) in the cluster of molecular ion
peak confirmed undoubtedly the structure of com-
pound 8. Owing to the presence of chlorine and sulfur
atoms in the molecule of 8, the ratio of [M + 2 + H]+
and [M + H]+ peaks intensities was 0.4 : 1. Using
procedure of direct admission of compound A, we
managed to detect the molecular ion peak [M]+ (m/z
168) corresponding to the structures B or C in the
mass spectrum recorded in a positive ion electrospray
ionization (HESI) mode.
Table 3. Crystal data of 2-amino-4-[(2-hydroxyethyl)sulfanyl]-
6-methylpyrimidine hydrochloride 9
Parameter
Formula
Crystal system
M
Value
C7H12N3OS·Cl
Monoclinic
221.71
Space group
a, Å
b, Å
P21/n
5.1668(4)
20.8004(13)
9.3735(6)
90
97.584(6)
90
998.57(12)
0.557
100(2)
c, Å
α, deg
β, deg
γ, deg
V, Å3
Pyrimidylthioethanol 7 was synthesized via S-alkyla-
tion of compound 4 with 2-chloroethanol in DMF in
the presence of potassium carbonate at 100°C. A
partial desulfurization of thione 4 occured when
replacing the used solvent and a basic agent with 10%
aqueous sodium hydroxide and reducing the reaction
temperature to 80°C. Polyethylene sulfide С2H4S was
isolated from the hot reaction mixture. Its melting
point (~154ºC) was close to that of one of the polymer
modifications [6]. After polyethylene sulfide separa-
tion and neutralization of the filtrate with acetic acid
the formed precipitate was filtered off and recrystal-
lized from water. The analysis of this precipitate by
HPLC-MS method showed the presence of 2-amino-6-
methylpyrimidin-4(3H)-one and of unreacted thione 4
identified as monoprotonated molecules [M + H]+ (m/z
126 and 142, respectively).
μ, mm–1
T, K
Z
d
4
calc, g cm–3
1.475
Crystal size, mm
Radiation
0.10 × 0.05 × 0.02
MoKα
Reflections collected
Independent reflections
2θ range, deg
Reflections with |F0| ≥ 4σF
Rint
7800
2291
5.88–55.00
1780
0.0588
Rσ
0.0816
R1 (|Fo| ≥ 4σF)
wR2 (|Fo| ≥ 4σF)
R1 (all data)
0.0425
0.0667
0.0638
wR2 (all data)
S
ρ
0.0745
1.052
–0.312, 0.356
The presumable mechanism of thione 4 desulfuriza-
tion involves several steps: nucleophilic addition of the
anion D to oxirane formed from 2-chloroethanol in the
presence of alkali, intramolecular cyclization of the
anion E to ionized spiro compound F, following
opening of the five-membered ring as a result of
redistribution of electron density, and the elimination
of thiirane from anion G with the final formation of
anion H.
min, ρmax, e/Å3
to the atom N1 showed that they had a less pro-
nounced ability to dissociate [pKa 4.66 (2a), 3.98 (3a)]
compared with the acids formed by the proton addition
to the atom N3 [pKа –1.26 (2a), –1.98 (3a)]. For
comparison, the pKa value for 2-amino-4-(methyl-
sulfanyl)pyrimidinium cation determined by potentio-
metric titration was 4.75 [9].
A similar mechanism has been proposed for desul-
furization of 2-thioxo-1,2-dihydropyrimidin-4(3H)-
ones by the action of oxiranes [7], which underlies the
modern procedure of uracil derivatives synthesis [8]
(Scheme 4).
The quaternization of compounds 2a–2d and 3a–3d
involving the N1 atom was confirmed by 13C NMR
spectroscopy data [5] for some of hydrochlorides 10a–
10d and 11a–11d. In the spectra of compounds 10a
and 11a of the signals of methyl group, C2 and C6
atoms of the pyrimidine ring were significantly shifted
to the strong field; the signal of C4 atom was shifted
downfield relative to the signals of the mentioned
atoms of thioethers 2a and 3a (Table 4, Scheme 5).
The preparation of hydrochlorides of thioethers 2a–
2d and 3a–3d was accomplished by their treating with
dry hydrogen chloride in anhydrous ethanol or benzene
at room temperature. The calculation of the pKa values
of their conjugate acids formed by the proton addition
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 6 2016

1278
ERKIN et al.
Cl
Cl
Crystal packing in compound 9.
Scheme 4.
RS−
S−
O
S
O−
S
−N
O
D
RO−
N
N
O
−
H
S
H2N
N
Me
H2N
N
Me
H2N
N
Me
E
F
G
R = 2-amino-6-methylpyrimidin-4-yl.
Of all the hydrochlorides synthesized only
compounds 11a and 11b were able to inhibit
completely (100%) the growth of Candida albicans
fungi (strain 15) in vitro in concentrations of 0.066 and
0.127 mmol/L, respectively. It should be noted that
hydrochlorides of benzyl ethers of 2-amino-5-bromo-6-
methylpyrimidin-4(3H)-thione [3], regardless of the
nature of the substituent in the aromatic moiety, were
inactive with respect to the fungi.
35ºC, 0.1% aqueous solution of trifluoroacetic acid–
acetonitrile, 95 : 5). Mass spectrum using the direct
admission of the sample was recorded on a tandem
quadrupole mass spectrometer Waters XEVO TQD in
HESI mode (anhydrous methanol, capillary voltage
4 kV, source temperature 150°C, desolvation gas
nitrogen). Elemental analysis was carried out using a
Flash EA 1112 analyzer. Elemental analysis of
polyethylene sulfide (C 39.36%; H 6.20%; S 52.49%)
was performed on a Leco CHNS-932 analyzer. The
chlorine content in compound 9 was determined by
Schoeniger method. TLC analysis was made using
EXPERIMENTAL
1H and 13C NMR spectra of solutions in DMSO-d6
were recorded on a Bruker Avance III-400 spectro-
meter operating at 400 (1H) and 100 (13C) MHz using
as internal reference the residual signals of undue-
terated solvent. IR spectra (KBr) were taken on a FSM
-1201 FTIR spectrometer. HPLC-MS spectra were
registered on a Thermo Scientific TSQ Quantum
Access instrument in HESI mode using methanol as a
solvent after preliminary chromatographic separation
of the samples (column Zorbax CB-C18, 150 × 2.1 mm,
Scheme 5.
Me
R
HN+
HCl
Cl−
2а−2d, 3а−3d
O
H2N
R = H (10a−10d), Br (11a−11d).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 6 2016
N
S
Ar

ARYL ETHERS OF 4-[(2-HYDROXYETHYL)SULFANYL]PYRIMIDINE DERIVATIVES
1279
Table 4. 13C NMR spectral data of 2-amino-4-[(2-aryloxy-
ethyl)sulfanyl]-5-R-6-methylpyrimidines 2a, 3a and their
hydrochlorides 10a and 11a
Sorbfil PTLC-AF-V-UV and Silufol UV-254 (10a–
10d) plates and eluting with acetone–hexane, 1 : 1
(eluent A) and 1-butanol–acetic acid–water, 1 : 1 : 1
(eluent B). Visualization of spots was performed with
UV light (λ = 254 nm). The charge calculation for the
Fletcher–Reeves optimized molecules was done with
the use of HyperChem software (Release 8.0.8); ioniza-
tion constants were calculated using Marvin program
[10]. Purification of the solvents was carried out in
accordance with the known methods [11].
δC, ppm
C2, C6
Comp. no.
Me
C4
2а
3а
10а
11а
23.66
24.37
19.06
22.51
163.1, 166.3
161.2, 164.4
155.5, 155.8
157.7а
168.3
167.1
177.9
176.0
a One of the signals was not observed due to the low intensity.
X-Ray diffraction analysis of the crystals of
compound 9 was done at the Resource Center of St.
Petersburg State University “X-ray diffraction studies”
using an Agilent Technologies Excalibur Eos diffrac-
tometer equipped with CCD detector. Diffraction data
were measured with monochromatic MoKα radiation at
100 K. The unit cell parameters (Table 3) were refined
by the least-squares method based on 7800 reflections
within 2θ 5.88–55.00º. The structure was solved by the
direct method and refined till R1 0.042 (wR2 0.067) for
1780 independent reflections with |F0| ≥ 4σF using
SHELXL program [12] integrated into the Olex2
software package [13]. The extinction correction was
empirically made basing on spherical harmonic
functions implemented in SCALE3 ABSPACK scaling
algorithm using CrysAlisPro software package
[Agilent Technologies, Ver. 1.171.36.20 (Release 27-
06-2012)]. Positions of the hydrogen atoms were
calculated by means of SHELX program, with Uiso(H) =
1.5Ueq(C) and C–H 0.96 Å for CH3 groups, Uiso(H) =
1.2Ueq(C) and C–H 0.97 Å for CH2 groups, Uiso(H) =
1.2Ueq(C) and C–H 0.93 Å for CH groups, Uiso(H) =
1.2Ueq(N) and N–H 0.86 Å NH and NH2 groups,
Uiso(H) = 1.5Ueq(O) and O–H 0.82 Å for OH groups.
The crystal data of compound 9 has been deposited at
the Cambridge Crystallographic Data Center (CCDC
1437521).
2-Amino-4-[(2-aryloxyethyl)sulfanyl]-5-bromo-6
-methylpyrimidines (3a–3d). A mixture of 0.3 g of
thioether 2a–2d and an equimolar amount of NBS [14]
in 15 mL of chloroform was refluxed for 1 h. Then the
solvent was removed in a vacuum, and the residue was
treated with 10% sodium hydroxide. The solid residue
was filtered off, washed with water, and dried at 70°C
to a constant weight. The product obtained was re-
crystallized from benzene–cyclohexane [5 : 2 (3a)], 3 :
2 (3b), 5 : 3 (3c)], or water–ethanol mixture, 1 : 3 (3d).
2-(2-Fluorophenoxy)ethyl chloride (5b). To a
solution of 0.85 g of freshly distilled thionyl chloride
in 15 mL of anhydrous chloroform precooled to 0–5ºC
was successively added 0.56 g of anhydrous pyridine.
Next a solution of 12.7 g of 2-(2-fluorophenoxy)
ethanol 6b in 15 mL of anhydrous chloroform was
added dropwise with vigorous stirring within 1 h,
maintaining the temperature of the reaction mixture
below 10°C. The resulting mixture was slowly heated
in a water bath to 60–65ºC and kept at this temperature
until gas evolution ceased. After distilling off the
volatiles, the residue was treated with 20 mL of water
and 20 mL of benzene, and the organic layer was
separated and dried over calcium chloride. Benzene
was distilled off, the residue was distilled, collecting
the fraction with bp 124–127ºC (35 mmHg). Yield
7.50 g (53%). Found, %: C 54.67; H 4.41. C8H8ClFO.
Calculated, %: C 55.03; H 4.62.
2-Amino-4-[(2-aryloxyethyl)sulfanyl]-6-methyl-
pyrimidines (2a–2d). An equimolar amount of the
corresponding 2-aryloxyethyl chloride 5a–5d and 0.49 g
of calcined potassium carbonate were added to a
suspension of 0.5 g (3.54 mmol) of thione 4 in 15 mL
of anhydrous DMF. The mixture was stirred at 100°C
for 1 h and then cooled. Inorganic salts were filtered
off. The filtrate was concentrated in a vacuum. The
solid residue was treated with 10% sodium hydroxide,
filtered off, washed with water, and dried at 70°C to a
constant weight. The product obtained was recrystal-
lized from benzene–cyclohexane mixture [2 : 1 (2a–
2c), 5 : 4 (2d)].
Compounds 5a, 5c and 5d were prepared similarly.
Their physicochemical characteristics coincided with
those given in [15, 16]. 2-Aryloxyethanols 6a–6d were
synthesized by the procedure reported in [17].
Physicochemical characteristics of the compounds
obtained coincided with those given in [18, 19].
2-Amino-4-[(2-hydroxyethyl)sulfanyl]-6-methyl-
pyrimidine (7). To a suspension of 4 g of thione 4 in
20 mL of anhydrous DMF were added 0.57 g of 2-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 6 2016

1280
ERKIN et al.
chloroethanol and 1 g of calcined potassium carbonate.
The mixture was vigorously stirred at 100°C for 1 h
and then cooled. Inorganic salts were filtered off. The
filtrate was concentrated in a vacuum. The oily residue
was treated with 5% sodium hydroxide. The precipitate
formed was filtered off, washed with water, and dried
at 70°C to a constant weight. Yield 0.82 g (62%), mp
118ºC, Rf 0.37 (A). An analytical sample was prepared
hydrogen chloride was bubbled to saturation. The
resulting slurry was cooled and kept at room tem-
perature for 20 h. The precipitate was filtered off,
washed with benzene, and dried at 70°C to a constant
weight to yield 90 mg (82%) of compound 11a [mp
164ºC, Rf 0.71 (B)] or 70 mg (63%) of compound 11b
[mp 130°C, Rf 0.61 (B)].
2-Amino-4-[(2-aryloxyethyl)sulfanyl]-5-bromo-6-
methylpyrimidine hydrochlorides (11c, 11d) were
prepared similarly from 60 mg of thioether 3c or 3d.
Yield 55 mg (83%) [11c, mp 179ºC, Rf 0.69 (B)], 50
mg (77%) [11d, mp 142ºC, Rf 0.66 (B)].
1
by recrystallization from water, mp 119ºC. H NMR
spectrum, δ, ppm: 2.14 s (3H, Me), 3.14 t (2H, CH2,
J = 6.5 Hz), 3.58 q (2H, CH2, J = 5.7 Hz), 4.86 s (1H,
OH), 6.33 s (1H, C5H), 6.40 s (2H, NH2). 13С NMR
spectrum, δC, ppm: 23.67 (Me), 31.33 (CH2), 60.54
(CH2), 106.4 (C5), 162.9, 166.1 (С2,6), 169.2 (С4).
Found, %: C 44.79; H 5.68; N 22.31. C7H11N3OS.
Calculated, %: C 45.39; H 5.99; N 22.68.
ACKNOWLEDGMENTS
The authors are grateful to V.V. Tets and co-
workers (Pavlov First Saint-Petersburg State Medical
University) for performing the microbiological tests, as
well as T.V. Artamonova (St. Petersburg State
University of Technology and Design) for performing
elemental analysis of polyethylene sulfide.
2-Amino-4-[(2-hydroxyethyl)sulfanyl]-6-methyl-
pyrimidine hydrochloride (9). Through a suspension
of 0.20 g of pyrimidylthioethanol 7 in 6 mL of
anhydrous benzene dry hydrogen chloride was bubbled
to saturation. The precipitate was filtered off, washed
with benzene, recrystallized from benzene–ethanol
mixture (5 : 3), and dried at 70°C to a constant weight.
REFERENCES
1
Yield 60 mg (27%), mp 189ºC, Rf 0.49 (A). H NMR
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spectrum, δ, ppm: 2.34 s (3H, Me), 3.28 t (2H, CH2,
J = 6.3 Hz), 3.64 t (2Н, CH2, J = 6.3 Hz), 6.84 s (1H,
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 6 2016