Alkylation of 6-Polyfluoroalkyl-2-thiouracils with Haloalkanes

Article abstract of DOI:10.1134/S1070428019060071

The structure of 6-polyfluoroalkyl-2-thiouracils and reactivity of nucleophilic centers in their molecules were analyzed by quantum chemical calculations. According to the experimental data, methylation of 6-polyfluoroalkyl-2-thiouracils with methyl iodide initially gives 2-methylsulfanyl-substituted pyrimidin-4-one and then S,N³- and S,O-dimethyl derivatives. The optimal conditions for the selective formation of the S, N³- isomer were heating in tert-butyl alcohol in the presence of cesium carbonate as a base. Ethylation of 6-polyfluoroalkyl-2-thiouracils afforded approximately equal amounts of S,N³- and S,O-dimethyl derivatives. S,N³-Dimethyl-substituted pyrimidines in boiling ethanol in the presence of potassium carbonate were converted into uracil potassium salts as a result of nucleophilic substitution of the methylsulfanyl group by ethoxy and subsequent dealkylation of the latter.

Full text of DOI:10.1134/S1070428019060071

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 6, pp. 782–791. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Organicheskoi Khimii, 2019, Vol. 55, No. 6, pp. 879–890.
Dedicated to Full Member of the Russian Academy of Sciences
O.N. Chupakhin on his 85th anniversary
Alkylation of 6-Polyfluoroalkyl-2-thiouracils with Haloalkanes
a
a
a
a
a
O. G. Khudina , A. E. Ivanova , Ya. V. Burgart , M. G. Pervova , T. V. Shatunova ,
b
b
a
S. S. Borisevich , S. L. Khursan , and V. I. Saloutin *
a
Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, Yekaterinburg, Russia
*
e-mail: saloutin@ios.uran.ru
b
Ufa Institute of Chemistry, Ufa Research Center, Russian Academy of Sciences, Ufa, Bashkortostan, Russia
Received April 15, 2019; revised April 23, 2019; accepted April 25, 2019
Abstract—The structure of 6-polyfluoroalkyl-2-thiouracils and reactivity of nucleophilic centers in their mole-
cules were analyzed by quantum chemical calculations. According to the experimental data, methylation of
6
-polyfluoroalkyl-2-thiouracils with methyl iodide initially gives 2-methylsulfanyl-substituted pyrimidin-4-one
3
and then S,N - and S,O-dimethyl derivatives. The optimal conditions for the selective formation of the
S,N - isomer were heating in tert-butyl alcohol in the presence of cesium carbonate as a base. Ethylation of
6
S,N -Dimethyl-substituted pyrimidines in boiling ethanol in the presence of potassium carbonate were con-
verted into uracil potassium salts as a result of nucleophilic substitution of the methylsulfanyl group by ethoxy
and subsequent dealkylation of the latter.
3
3
-polyfluoroalkyl-2-thiouracils afforded approximately equal amounts of S,N - and S,O-dimethyl derivatives.
3
Keywords: 6-polyfluoroalkyl-2-thiouracils, methylation, ethylation, quantum chemical calculations, nucleo-
philic substitution, dealkylation.
DOI: 10.1134/S1070428019060071
Pyrimidine ring is the key structural unit of many
drugs such as barbiturates (phenobarbital, hexo-
barbital), sulfanylamides (sulfadimethoxine, sulfa-
diazine), antiviral agents (zidovudine, lamivudine), and
metabolic stimulators (6-methyluracil, pentoxifylline).
Modern antitumor agents include pyrimidine deriva-
tives acting as nucleic acid exchange antimetabolites
Candida albicans, Candida lunata, Aspergillus niger,
and Aspergillus flavus [6]. Ethyl 3-[4-hydroxy-6-(tri-
fluoromethyl)pyrimidin-2-yl]sulfanyl}propanoate
exhibited anti-inflammatory activity and selectively
inhibited cyclooxygenase-1/2 and lipoxygenase in vitro
[7]. 2-[(Naphthalen-2-ylmethyl)sulfanyl]-6-(trifluoro-
methyl)pyrimidin-4-amine inhibited HIV-1 reverse
transcriptase [8].
(
uramustine, 5-fluorouracil) [1, 2]. Introduction of
a polyfluoroalkyl group and a thioxo functionality into
the pyrimidine ring also gives rise to a broad spectrum
of biological activity. For example, 6-trifluoromethyl-
The diversity of biological activity of 2-thiouracils
and their S-substituted analogs prompted us to study
the reactivity of nucleophilic centers in polyfluoro-
alkyl-substituted 2-thiouracils 1 by quantum chemical
calculations, as well as experimentally, by carrying out
their alkylation. It is known that organofluorine com-
pounds are of particular interest from the viewpoint of
design of new pharmaceuticals and materials due to
electronegativity of fluorine atoms that could modify
chemical, physical, and biological characteristics of
newly formed fluorine-containing molecules [9].
2
-thiouracil showed a high in vitro and in vivo anti-
parasitic activity against Toxoplasma gondii [3], and
-heptafluoropropyl-2-thiouracil was recommended as
6
an antithyroid agent [4]. 2-(4-Methoxybenzylsulfanyl)-
and 2-[1-oxo-1-(piperidin-1-yl)ethylsulfanyl]-6-tri-
fluoromethylpyrimidin-4-ones displayed a high inhib-
itory activity toward fatty acid-binding proteins, which
may be efficient in the treatment of type II diabetes
[
5]. N-[4-(1H-Benzimidazol-2-yl)phenyl]-2-{[4-(hy-
droxy)-6-(trifluoromethyl)pyrimidin-2-yl]sulfonyl}-
acetamide showed a high antifungal activity against
Theoretically, 6-polyfluoroalkyl-2-thiouracils can
exist as 8 different tautomers A–H due to acidity of the
7
82

ALKYLATION OF 6-POLYFLUOROALKYL-2-THIOURACILS WITH HALOALKANES
783
Scheme 1.
F3C
O
F3C
O
F3C
O
F3C
OH
5
2
4
6
HN1
3NH
HN
N
N
NH
N
NH
S
SH
1a, B
66.1
SH
1a, C
24.4
S
1
a, A
1a, D
∆G, kJ/mol
0.0
79.5
F3C
OH
F3C
O
F3C
OH
F3C
OH
HN
N
N
NH
N
N
N
N
S
S
1a, F
66.6
S
SH
1a, H
27.4
1
a, E
1a, G
∆G, kJ/mol
53.4
136.4
two NH protons (Scheme 1). The thermodynamic
stability of tautomers A–H was estimated by quantum
chemical calculations using 6-trifluoromethyl-2-thio-
uracil 1 as model compound. The results showed that
structure A is the most energetically favorable (the
differences in the Gibbs energies calculated in the ideal
gas approximation are given in Scheme 1).
2-Thiouracils 1 possess five nucleophilic centers
1
3
5
(N , N , S, O, C ); therefore, their alkylation could lead
to the formation of four regioisomeric monoalkyl
derivatives and six dialkyl-substituted isomers. In
order to evaluate the reactivity of these centers in the
molecule of 6-trifluoromethyl-2-thiouracil (1a), we
calculated their local reactivity indices for tautomer A
in the ideal gas approximation (Table 1). It was found
that the most nucleophilic in structure A is the sulfur
The IR and NMR spectra of 1a and 1b and X-ray
diffraction data for 1a [10] also indicated that they
exist in solution and in crystal as 2-thioxo-2,3-dihydro-
pyrimidin-4(1H)-ones (structure A in Scheme 1). The
IR spectra of both crystalline samples of 1a and 1b and
their solutions in acetonitrile contained lactam car-
1
3
atom, N and N atoms are less nucleophilic, and O
5
and C are weakly electrophilic.
The reactivity of nucleophilic centers of 2-thio-
uracils 1 was studied experimentally by analyzing
products of their alkylation with methyl iodide and
ethyl iodide. According to published data, methylation
of 6-trifluoromethyl-2-thiouracil (1a) with methyl
iodide in THF in the presence of a base [11] and with
dimethyl sulfate under alkaline conditions (NaOH,
–
1
bonyl band at 1683–1689 and 1717–1719 cm , respec-
1
tively. The H NMR spectra of 1a and 1b in DMSO-d
6
displayed a signal of 5-H at δ 6.37–6.41 ppm and
downfield singlets typical of NH groups at δ 12.76–
1
3
1
2.85 and 13.40–13.48 ppm. In the C NMR spectrum
of 1a (DMSO-d ), the C=S carbon atom resonated at
H O) [12] involves the sulfur atom to give 2-methyl-
2
6
δC 176.8 ppm, and the carbonyl carbon signal appeared
sulfanyl derivative 2. In our experiments, thiouracil 1a
at δ 159.9 ppm.
was alkylated with excess methyl iodide (3 equiv) in
C
Table 1. Fukui indices of the reaction centers of thiouracil 1a (tautomer A)
Atom
q
N+1
q
N
q
N–1
f
i+
f
i–
Δf
5
C
–0.412
–0.382
–0.702
–0.576
–0.648
–0.305
–0.133
–0.563
–0.584
–0.618
–0.258
–0.458
–0.446
–0.543
–0.583
0.107
0.249
0.047
0.591
0.117
0.041
0.035
0.060
–0.342–
0.022
S
O
0.139
1
N
–0.008–
0.030
–0.049–
–0.005–
3
N
a
N
q , qN–1, and qN +1 are the charges on an atom in the neutral molecule, radical cation, and radical anion, respectively; fi+ and fi– are the
Fukui indices for nucleophilic and electrophilic attack respectively; ∆f are the Fukui dual descriptors: if ∆f > 0, nucleophilic attack is
preferred, and if ∆f < 0, electrophilic attack is preferred.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019

7
84
KHUDINA et al.
Scheme 2.
F3C
O
MeI, K CO , THF, 20°C
2
3
or MeI, K CO , MeCN, –15°C
2
3
N
NH
SMe
(52 or 74%)
2
RF
O
RF
O
RF
OR
AlkI (excess), K CO
2
3
MeCN, reflux
HN1 3NH
N
N
N
N
+
Alk = Me, Et
R
S
a, 1b
SR
3a–3c (25–74%)
SR
4a–4c (5–51%)
1
MeI, K CO , MeCN, 25°C
2
3
2
+
3a
+
4a
1
, R
F
= CF
3
(a), C
3
F
7
(b); 3, 4, R = Me (a, b), Et (c); R
F
3 3 7
= CF (a, c), C F (b).
the presence of K CO in THF at 20°C or in aceto-
was obtained in the system t-BuOH/Cs CO which
2 3
2
3
nitrile at –10 to –15°C to produce the same compound
Scheme 2). 2-Methylsulfanylpyrimidine 2 was also
ensured a 3a:4a ratio of 40.5:1 and an overall yield of
85% (Table 2). These conditions can be regarded as
optimal for the selective formation of isomer 3a.
(
synthesized by us previously [13] by condensation of
ethyl 4,4,4-trifluoro-3-oxobutanoate with S-methyliso-
thiourea hydrogen sulfate in a potassium carbonate
solution, and spectral characteristics of samples of 2
obtained by different methods were identical.
Thus, we have shown that the alkylation of thio-
uracil 1a with excess methyl iodide in acetonitrile in
the presence of K CO at –10 to –15°C gives 2-meth-
2
3
ylsulfanyl derivative 2 and that in boiling acetonitrile,
a mixture of dimethyl-substituted pyrimidines 3a and
4a is formed (Scheme 2). The methylation of 1a was
also carried out in MeCN/K CO at 25°C. After 3 h,
When the reaction of thiouracils 1a and 1b with
3
equiv of methyl iodide was carried out in acetonitrile
in the presence of potassium carbonate, the products
2
3
were mixtures of isomeric dimethyl derivatives 3a, 3b
the reaction mixture contained compounds 2, 3a, and
4a at a ratio of 24:65:11 (according to the GLC data).
The results obtained at room temperature provide
an experimental proof of the following reaction
mechanism: initially formed thiouracil potassium salt I
is methylated first at the most nucleophilic sulfur atom,
(
68–74%) and 4a, 4b (5–9%) (Scheme 2). With the
goal of finding conditions for the selective formation
of one of the isomers, different solvents and bases
were tried. The product mixtures were analyzed by
GC/MS. The best results with the highest overall
yields are summarized in Table 2.
3
and further methylation involves the N and 4-O com-
petitive centers with predominant formation of
N -methyl isomer 3a (Scheme 3).
The highest substrate conversion (99%) was
achieved in the reactions of 1a and 1b with methyl
iodide in acetone or acetonitrile in the presence of
K CO or Cs CO , and in all cases isomers 3 were the
3
We have found no published data on ethylation
of 6-trifluoromethyl-2-thiouracil (1a), though it was
proposed previously to synthesize 2-ethylsulfanyl-6-
trifluoromethylpyrimidin-4-one by cyclization of ethyl
4,4,4-trifluoro-3-oxobutanoate with S-ethylisothiourea
[14]. The ethylation of thiouracil 1a with ethyl iodide
was carried out under different conditions, and the
reaction mixtures were analyzed by GC/MS. The
results with the maximum overall yield are given in
Table 3. The alkylation of 1a with ethyl iodide led to
the formation of comparable amounts of isomers 3c
and 4c. In the reactions in acetone and acetonitrile in
the presence of Na CO isomer 3c slightly prevailed,
2
3
2
3
major products. The ratio 3:4 changed insignificantly,
from 3.6 :1 to 4.6:1 for compounds 3a and 4a and
from 5.4:1 to 5.8:1 for 3b and 4b. In the presence of
Na CO as a base, the conversion and reaction rate
2
3
were lower, but the ratio 3a:4a increased (6.2:1 to
.8:1). The reactions in alcohols were more selective;
6
however, the overall yield decreased and depended on
the alcohol nature. In the reactions in ethanol, the
overall yield almost did not depend on the metal car-
bonate (40–46%), whereas in tert-butyl alcohol the
overall yield considerably increased (from 3 to 85%)
as the metal cation radius increased. The best result
2
3
and the ratio 3c/4c was 1.1:1 to 1.4:1, whereas in the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019

ALKYLATION OF 6-POLYFLUOROALKYL-2-THIOURACILS WITH HALOALKANES
785
Table 2. Methylation of thiouracils 1a and 1b with methyl iodide (GLC data)
a
Thiouracil no.
Solvent/base
Temperature, °C Reaction time, h Product ratio 3/4 Overall yield (3+4), %
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
b
b
b
Me
Me
Me
2
2
2
CO/Na
CO/K CO
CO/Cs CO
CO
CO
MeCN/Cs CO
THF/K CO
EtOH/Na
EtOH/K
EtOH/Cs
t-BuOH/Na
t-BuOH/K CO
t-BuOH/Cs CO
t-BuOH/NaOH
1,4-Dioxane/K
Me CO/K CO
MeCN/K CO
EtOH/K CO
2
CO
3
56
56
56
82
82
82
66
78
78
78
83
83
83
83
1010
56
82
78
4
2
4
6
1
2
6
5
5
5
3
5
7
5
1
1
1
2
6.8:1
4.6:1
3.7:1
6.2:1
4.1:1
3.6:1
17:1
88
99
99
78
99
99
86
40
43
46
03
38
85
05
2
3
2
3
MeCN/Na
MeCN/K
2
3
2
3
2
3
2
3
2
CO
3
16.5:1
12.5:1
14.9:1
1:0
2
CO
CO
CO
3
2
3
2
3
2
3
49.7:1
40.5:1
3.2:1
2
3
2
CO
3
No reaction
2
2
3
5.8:1
5.4:1
99
99
40
2
3
2
3
15.4:1
a
Boiling point of the solvent is given.
presence of K CO and Cs CO the isomer ratio
changed to the opposite, 3c/4c 1:1.3 to 1:1.9. The
overall yield 3c and 4c in alcohols decreased to 35–
sulfanyl group resonated at δ 2.56–2.63 ppm, whereas
the MeN signal of 3a and 3b was located at δ 3.54–
3.55 ppm, and the MeO signal of 4a and 4b, at
δ 4.03 ppm.
2
3
2
3
4
1%, though the reaction was more selective in favor
1
of isomer 3c (3c/4c 4.2:1 to 21.4:1; Table 3).
The H NMR spectra of S,N- and S,O-diethyl deriv-
It was convenient to determine the structure of
regioisomeric dialkyl derivatives 3a–3c and 4a–4c by
IR spectroscopy since the IR spectra of S,O-dimethyl
isomers 4a–4c lacked lactam carbonyl band which
appeared in the spectra of S,N-dimethyl derivatives
atives 3c and 4c in CDCl displayed an insignificant
3
difference in the chemical shifts of the methylene
protons of the EtS substituent (δ 3.15 and 3.23 ppm),
as well as of the EtN and EtO groups (δ 4.11 and
4.47 ppm, respectively). The SCH and NCH carbons
2
2
–
1
1
13
3
3
a–3c at 1696–1699 cm . In the H NMR spectra of
resonated in the C NMR spectrum of 3c at δ 26.91
C
a, 3b, 4a, and 4b in CDCl , protons of the methyl-
and 40.12 ppm, respectively, and the SCH and OCH
3
2
2
Scheme 3.
F3C
O
K CO , MeCN
F3C
O
F3C
O
2
3
2
5°C
MeI (excess)
HN
NH
N
NH
N
NH
SMe
–
+
S
S K
1
a
I
2
F3C
O
F3C
OMe
MeI (excess)
+
N
N
N
N
Me
SMe
SMe
4a
3
a
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019

7
86
KHUDINA et al.
Table 3. Ethylation of thiouracil 1a with ethyl iodide (GLC data)
a
Solvent/base
Temperature, °C
Reaction time, h
Product ratio 3c:4c
Overall yield (3c+4c), %
Me
Me
Me
2
2
2
CO/Na
CO/K CO
CO/Cs CO
CO
CO
MeCN/Cs CO
EtOH/Na CO
EtOH/K CO
EtOH/Cs
2
CO
3
56
56
56
82
82
82
78
78
78
83
5
4
3
6
3
1
1
3
3
3
1.4:10.
0.1:1.3
0.1:1.6
0.1.1:1
0.1:1.9
0.1:1.3
17.9:10.0
21.4:10.0
4.2:10.
5:1
68
82
94
40
91
92
40
41
35
36
2
3
2
3
MeCN/Na
MeCN/K
2
3
2
3
2
3
2
3
2
3
2
CO
3
2 3
t-BuOH/Cs CO
a
Boiling point of the solvent is given.
signals of 4c were observed at δ 25.42 and
kov [17] earlier reported the formation of only one
S,N -dimethyl isomer in this reaction. The S,O-di-
C
3
6
3.42 ppm, respectively; i.e., in the regions typical of
the corresponding fragments.
methyl isomer was synthesized by Senda and Suzui
[18] by methoxylation of 4-chloro-6-methyl-2-(meth-
ylsulfanyl)pyrimidine.
1
9
In the F NMR spectra of 3a and 3c we observed
neither splitting of the CF signal nor its shift
3
(
δ 89.91, 89.80 ppm; CDCl ) relative to the corre-
We have found that the low overall yield of com-
pounds 3b and 4b (40%, Table 1) in the alkylation of
thiouracil 1b with methyl iodide in ethanol in the
presence of K CO is related to further transformations
F
3
sponding signal of 2-(methylsulfanyl)-6-(trifluoro-
methyl)pyrimidin-4(3H)-one (δ 89.88 ppm; CDCl )
F
3
[13], which would be expected if the CF group were
3
1
2
3
3
located closely to alkyl substituent on N . This means
that the alkyl group is attached to N .
of S,N -isomer 3b. After 2 h, GC/MS analysis of the
reaction mixture revealed a ion peak with m/z 322 cor-
3
+
responding to the molecular ion [M] of 2-ethoxypy-
It should be noted that S,O-dimethylpyrimidine 4a
was synthesized previously [15] by a different method
from 4-chloro-2-(methylsulfanyl)-6-(trifluoromethyl)-
pyrimidine, but the product was characterized only by
elemental analysis and melting point. According to
Bhabak and Mugesh [16], methylation of 6-methyl-2-
thiouracil with methyl iodide in acetone in the pres-
rimidinone J (R = C F ), and 6-(heptafluoropropyl)-3-
F
3 7
+
methyluracil K (R = C F , m/z 294 [M] ) was detected
F
3 7
in the reaction mixture after 4 h (Scheme 4).
By specially heating compounds 3a and 3b in anhy-
drous ethanol in the presence of potassium carbonate
we obtained uracil potassium salts 6a and 6b, and in
the reaction with 3a we succeeded in isolating interme-
diate product, 2-ethoxy-3-methyl-6-(trifluoromethyl)-
1
ence of potassium hydroxide gave two isomeric S,N -
and S,N -dimethyl derivatives, though Erkin and Kruti-
3
Scheme 4.
RF
O
RF
O
RF
O
N
N
HN
N
N
K+
N
Me
Me
Me
K CO , EtOH (anhydrous)
2
3
OEt
O
O
reflux
3
a, 3b
J
K
6a, 6b (66–73%)
F3C
O
N
N
Me
OEt
(32%)
5
3
F 3 3 7
, 6, R = CF (a), C F (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019

ALKYLATION OF 6-POLYFLUOROALKYL-2-THIOURACILS WITH HALOALKANES
787
1
pyrimidin-4-one (5) (Scheme 4). The H NMR spec-
trum of 5 showed a singlet at δ 3.44 ppm due to the
NMe group and a triplet and a quartet at δ 1.45 and
in the anion of 6a is strongly delocalized (Fig. 1).
Analysis of the electron density distribution suggests
two most probable positions of potassium ion: between
2
3
6
4
.54 ppm, respectively, typical of ethoxy group.
the O and N atoms (structure L) or at the O atom
structure M). Structure L is more thermodynamically
(
Acid-catalyzed hydrolysis of methylsulfanylpyrimi-
stable (Scheme 5).
dines is widely used to obtain uracils [19, 20]. How-
ever, we believe that in the above reactions uracils 6a
and 6b are formed along a different path. Presumably,
the first stage is nucleophilic substitution of the MeS
group by the solvent to give intermediate 2-ethoxypy-
rimidinone J (compound 5 was isolated in the reaction
with 3a; Scheme 4). Nucleofugality of methylsulfanyl
group is well known. For example, we previously
showed [13] the possibility of substitution of the
Scheme 5.
–
O K+
F3C
O
F3C
N
K+
O
N
N
N
Me
Me
O
L
6a
M
∆G, kJ/mol
0.0
23.2
2
-MeS group in 6-(polyfluoroalkyl)pyrimidin-4-ones
Thus, the results of quantum chemical calculations
and experimental data showed that 6-polyfluoroalkyl-
by a hydrazine or morpholine fragment. Replacement
of the 2-MeS group in pyrido[3,4-d]pyrimidin-4-one
by ethoxy on heating in ethanolic sodium ethoxide
under microwave irradiation was described in [21].
2
-thiouracils exist as 6-(polyfluoroalkyl)-2-sulfanyli-
dene-2,3-dihydropyrimidin-4(1H)-one tautomers. Our
results and published data [6–8, 11, 12] indicated that
polyfluoroalkyl-substituted thiouracils are alkylated
first at the most nucleophilic sulfur atom. However, we
found that in basic medium (especially on heating)
further alkylation of the S-alkyl derivatives involves
The next stage is likely to be dealkylation of the
ethoxy group in intermediate J by the action of ethanol
as nucleophile on the α- or β-carbon atom of the ethyl
group according to the S 2 or E2 mechanism to form
intermediate uracil K which we failed to isolate
because of its rapid transformation to potassium salt 6
N
3
the N and O atoms and that methylation gives prefer-
3
entially S,N -dimethyl isomers, whereas ethylation
(
Scheme 4). The possibility of dealkylation according
leads to the formation of approximately equal amounts
to the proposed scheme was described previously by
Dean and Papadopoulos [22] for 3-benzyl-2-ethoxy-
quinazolin-4-one on heating with benzylamine to
3
of S,N - and S,O-diethyl derivatives. The observed
difference in the alkylation directions may be related to
steric hindrances created by bulkier ethyl group on the
sulfur atom to attack of the alkylating agent on the
neighboring nitrogen atom. Furthermore, the methyl-
1
50°C or with morpholine to 100°C. The authors
believed that the attack of nucleophiles, benzylamine
and morpholine, is directed at the α- or β-carbon atom
of the ethyl group rather than at C to give 3-benzyl-
quinazoline-2,4-dione due to steric hindrances in
3
sulfanyl group in S,N -dimethylpyrimidines is substi-
2
tuted by ethoxy on heating in ethanol under basic
conditions, followed by dealkylation of the ethoxy
fragment to afford uracil potassium salts.
3
-benzyl-2-ethoxyquinazolin-4-one.
Salts 6a and 6b were characterized by IR and NMR
–
0.402
spectra and elemental analyses. Their IR spectra con-
tained a lactam carbonyl band at 1654–1668 cm ,
which is shifted to lower frequencies relative to the
–
1
1
C=O band of 3a and 3b. In the H NMR spectra of
6
a and 6b in DMSO-d we observed a singlet of the
6
–
0.116
NMe group at δ 3.06 ppm and a singlet of 5-H at
δ 5.47 ppm. The C NMR spectrum of 6b showed
1
3
a signal at δ 26.54 ppm, which is typical of NMe
C
carbon atom.
Potassium salts 6a and 6b could have different
structures, depending on localization of the negative
charge. It was disfficult to unambiguously determine
their structure on the basis of spectral data. According
to quantum chemical calculations, the negative charge
–0.206
–0.404
Fig. 1. Negative charge distribution in the anion of uracil
potassium salt 6a.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019

7
4
88
KHUDINA et al.
EXPERIMENTAL
The Fukui function [26] for a reaction center can be
represented as f = q + q
+
A
A
for nucleophilic attack
A
N
N+1
–
A
A
A
The NMR spectra were recorded on Bruker DRX-
and f = q
q
– q for electrophilic attack, where q ,
are the charges on an atom in the
N–1
A
N – 1
A
N
N
1
19
A
00 (400 MHz for H and 376 MHz for F) and
N+1, and q
1
Bruker Avance 500 spectrometers (500 MHz for H,
neutral molecule, radical anion, and radical cation,
respectively.
1
9
13
4
70 MHz for F, and 126 MHz for C); the chemical
1
shifts were measured relative to tetramethylsilane ( H),
The Fukui dual descriptor is calculated as follows:
1
9
13
hexafluorobenzene ( F) or the solvent signal ( C;
+
A
–
A
A
N
A
A
A
N
CDCl , DMSO-d ). The IR spectra were recorded on
a Perkin Elmer Spectrum One spectrometer in the
Δf
A
= f
– f
= (q
– qN + 1) – (qN – 1 – q
)
3
6
A
A
A
= 2q
N
– qN + 1 – qN – 1.
–
1
range 4000–400 cm using a diffuse reflectance acces-
sory, as well as on a Thermo Electron Corporation
Nicolet 6700 spectrometer with Fourier transform
equipped with an ATR accessory. The elemental anal-
yses (C, H, N) were obtained with a Perkin Elmer 2400
Series II analyzer. The melting points were measured
in open capillaries on a Stuart SMP30 melting point
apparatus. Silicagel 60 (0.063–0.02 mm, Merck) was
used for column chromatography.
2
-Sulfanylidene-6-(trifluoromethyl)-2,3-dihydro-
pyrimidin-4(1H)-one (1a) was synthesized as de-
scribed in [10]. Neither IR nor NMR spectra of 1a
were given in previous publications [10, 27]. IR spec-
trum (DR), ν, cm : 3128, 3064, 2968, 2895 (NH, CH),
689 (C=O), 1655, 1582 (C=N, C=C, δNH), 1090–
210 (C–F). H NMR spectrum (DMSO-d ), δ, ppm:
.41 d (1H, 5-H, J = 1.4 Hz), 12.85 s (1H, NH),
3.48 br.s (1H, NH). C NMR spectrum (DMSO-d ),
δ , ppm: 105.17 q (C , J = 3.8 Hz), 118.85 q (CF , J =
–
1
1
1
6
1
1
6
1
3
6
5
The reaction mixtures were analyzed by GLC on
a Shimadzu GC 2010Plus gas chromatograph equipped
with a flame ionization detector and a ZB-5 capillary
column (30 m×0.25 mm, film thickness 0.25 μm);
oven temperature programming from 40°C (3 min) to
C
3
6
4
2
(
(
1
[
6
75 Hz), 140.57 q (C , J = 36 Hz), 159.86 (C ), 176.85
2
19
C ). F NMR spectrum (DMSO-d ): δ 94.47 ppm
6 F
+
·
CF ). Mass spectrum, m/z (I , %): 196 (83) [M] ,
3 rel
+
+
77 (3) [M – F] , 163 (4) [M – HS] , 149 (4)
M – CH SH] , 138 (29) [M – NCS] , 69 (13) [CF ] ,
8 (100) [C H NCO] , 45 (3) [CHS] .
2 2
+
+
+
2
80°C at a rate of 10 deg/min, followed by 30 min at
2
3
+
+
the final temperature; injector temperature 250°C,
detector temperature 300°C; carrier gas nitrogen, split
ratio 1:30, flow rate 1.0 mL/min. The mass spectra
were recorded with a Trace GC Ultra DSQ II gas
chromatograph coupled with a quadrupole MS detector
6
-(Heptafluoropropyl)-2-sulfanylidene-2,3-dihy-
dropyrimidin-4(1H)-one (1b). A mixture of ethyl
,4,5,5,6,6,6-heptafluoro-3-oxohexanoate (4.262 g,
5 mmol), thiourea (1.52 g, 20 mmol), and 2 M etha-
nolic sodium ethoxide (15 mL) was refluxed for 20 h.
The solvent was removed under reduced pressure, the
residue was dissolved in distilled water, and the
solution was acidified with glacial acetic acid and left
overnight. The precipitate was filtered off, washed
with water, and recrystallized from acetic acid. Yield
4
1
(
Thermo TR-5MS capillary column, 30 m×0.25 mm,
film thickness 0.25 μm; oven temperature program-
ming from 40°C (3 min) to 280°C at a rate of 10 deg×
–
1
min , followed by 40 min at the final temperature;
injector temperature 250°C, interface temperature
2
30°C, ion source temperature 200°C; carrier gas
helium, split ratio 1:50, flow rate 1.0 mL/min; electron
impact, 70 eV, a.m.u. range 20–1000).
2
.088 g (47%), white powder, mp 229–231°C. IR
spectrum (ATR), ν, cm : 3128, 3072, 2952, 2883 (NH,
CH), 1683 (C=O), 1122–1233 (C–F). H NMR spec-
–
1
1
Quantum chemical calculations. The calculations
(
geometry optimization and solution of vibrational
trum (DMSO-d
(1H, NH), 13.40 br.s (1H, NH). F NMR spectrum
(DMSO-d ), δ , ppm: 37.15 m (2F, CF ), 46.92 m (2F,
CF ), 82.97 t (3F, CF , J = 9.3 Hz). Mass spectrum,
6
), δ, ppm: 6.37 s (1H, 5-H), 12.76 s
1
9
problem) were carried out using GAUSSIAN 09
software package [23] with the TPSS functional [24]
and 6-311+G(d,p) basis set [25]. The thermodynamic
parameters of different tautomers of 1a were deter-
mined, and NBO analysis of the reaction centers
therein was performed, for the isolated molecule.
Potassium salts 6a and 6b were calculated with
account taken of solvent effects (according to the PCM
model [26]; temperature 298.15 K; pressure 1 atm;
solvent ethanol).
6
F
2
2
3
+·
+
m/z (I , %): 296 (41) [M] , 263 (2) [M – HS] (2),
49 (2) [M – CH SH] , 238 (22) [M – NCS] , 69 (16)
rel
+
+
2
[
%
%
2
+
+
+
CF ] , 68 (100) [C H NCO] , 45 (4) [CHS] . Found,
3 2 2
: C 28.56; H 1.12; N 9.39. C H F N OS. Calculated,
7 3 7 2
: C 28.39; H 1.02; N 9.46.
Alkylation of thiouracils 1a and 1b (general
procedures). a. A mixture of thiouracil 1a (200 mg,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019

ALKYLATION OF 6-POLYFLUOROALKYL-2-THIOURACILS WITH HALOALKANES
789
–
1
1
mmol), methyl iodide (426 mg, 3 mmol), and potas-
cm : 3085, 2939 (CH), 1699 (S=O), 1516 (C=N,
1
sium carbonate (276 mg, 2 mmol) in THF (15 mL) was
stirred for 40 min at 20°C. The precipitate was filtered
off, excess methyl iodide and the solvent were distilled
off from the filtrate under reduced pressure, and the
product (compound 2) was isolated from the residue by
column chromatography using chloroform–ethyl
acetate (1:1) as eluent.
C=C), 1100–1227 (C–F). H NMR spectrum (CDCl ),
δ, ppm: 2.60 s (3H, SCH ), 3.55 s (3H, NCH ), 6.59 s
(1H, 5-H). F NMR spectrum (CDCl ), δ , ppm:
35.50 m (2F, CF ), 43.92 m (2F, CF ), 81.42 t (3F, CF ,
3
3
3
1
9
3
F
2
2
3
J = 9.2 Hz). Mass spectrum, m/z (I , %): 324 (30)
rel
+
·
+
+
[M]
,
309 (4) [M – CH ] , 305 (<1) [M – F] , 295 (1)
3
+
+
+
[M – HCO] , 291 (2) [M – HS] , 279 (100) [M – CHS] ,
38 (5) [M – NCS – C H ] , 69 (29) [CF ] , 68 (15)
+
+
2
[
b. A mixture of thiouracil 1a (200 mg, 1 mmol),
methyl iodide (426 mg, 3 mmol), and potassium car-
bonate (276 mg, 2 mmol) in acetonitrile (15 mL) was
stirred for 3 h at –10 to –15°C. The precipitate was
filtered off, excess methyl iodide and the solvent were
distilled off from the filtrate under reduced pressure,
and the product (compound 2) was isolated from the
residue by column chromatography using chloroform–
ethyl acetate (1:1) as eluent.
2 4 3
+
+
C H NCO] , 45 (17) [CHS] . Found, %: C 33.61;
2 2
H 2.19; N 8.45. C H F N OS. Calculated, %: C 33.34;
9
7
7
2
H 2.18; N 8.64.
-Ethyl-2-(ethylsulfanyl)-6-(trifluoromethyl)-
pyrimidin-4(3H)-one (3c). Yield 63 mg (25%) (c),
3
–
1
colorless oil, mp 21–22°C. IR spectrum (neat), ν, cm :
2981, 2937 (CH), 1698 (C=O), 1505 (C=N, C=C),
1070–1183 (C–F). H NMR spectrum (CDCl ), δ,
1
3
ppm: 1.34 t (3H, SCH CH , J = 7.3 Hz), 1.41 t (3H,
2
3
c. A mixture of thiouracil 1a or 1b (1 mmol),
methyl or ethyl iodide (3 mmol), and potassium car-
bonate (276 mg, 2 mmol) in acetonitrile (15 mL) was
refluxed for 1–3 h. The precipitate was filtered off, and
the filtrate was concentrated. The products were isolat-
ed by column chromatography using hexane–ethyl
acetate at a ratio of 4:1 as eluent for compounds 3a,
NCH CH , J = 7.3 Hz), 3.23 q (2H, SCH , J = 7.3 Hz),
2
3
2
4
.11 q (2H, NCH , J = 7.3 Hz), 6.52 s (1H, 5-H).
2
1
3
C NMR spectrum (CDCl ), δ , ppm: 12.13 (CH ),
3
C
3
1
3.60 (CH ), 26.91 (SCH ), 40.12 (NCH ), 107.31 q
3 2 2
5
(
C , J = 3.5 Hz), 120.34 q (CF , J = 274.7 Hz),
3
6
4
2
1
50.44 q (C , J = 35.5 Hz), 161.13 (C ), 164.70 (C ).
F NMR spectrum (CDCl ): δ 89.80 ppm, s (CF ).
1
9
3
F
3
3
c, 4a, and 4c or at a ratio of 6:1 for 3b and 4b.
-(Methylsulfanyl)-6-(trifluoromethyl)pyrimi-
din-4(3H)-one (2). Yield 109 mg (52%) (a), 155 mg
74%) (b); white powder, mp 178–180°C [13]. Mass
+
·
Mass spectrum, m/z (I , %): 252 (23) [M] , 233 (8)
rel
2
+
+
+
[M – F] , 224 (25) [M – CO] , 223 (79) [M – C H ] ,
2 5
+
+
2
19 (15) [M – HS] , 191 (40) [M – C H S] , 163 (100)
2 5
(
+
+
[C H F N O] , 138 (21) [M – NCS – C H ] , 69 (17)
5 2 3 2 4 8
+
·
spectrum, m/z (I , %): 210 (100) [M] , 190 (16)
+
+
+
rel
[CF ] , 68 (31) [C H NCO] , 45 (12) [CHS] . Found,
3 2 2
+
+
+
[M – HF] , 177 (2) [M – HS] , 163 (40) [M – CH S] ,
3
%
: C 43.06; H 4.33; N 11.17. C H F N OS. Calcu-
9 11 3 2
+
+
1
38 (14) [M – NCS,CH ] , 69 (9) [CF ] , 68 (16)
2 3
lated, %: C 42.85; H 4.40; N 11.11.
+
+
[C H NCO] , 46 (9) [CH S] .
2 2 2
4
-Methoxy-2-(methylsulfanyl)-6-(trifluoro-
3
-Methyl-2-(methylsulfanyl)-6-(trifluoromethyl)-
methyl)pyrimidine (4a). Yield 20 mg (9%) (c),
pyrimidine-4(3H)-one (3a). Yield 152 mg (68%) (c),
white powder, mp 83–85°C. IR spectrum (DR), ν,
colorless oil; published data [15]: mp 36–37°C.
1
H NMR spectrum (CDCl ), δ, ppm: 2.58 s (3H,
3
–
1
1
9
cm : 3065, 2937 (CH), 1696 (C=O), 1519 (C=N,
SCH ), 4.03 s (3H, OCH ), 6.69 s (1H, 5-H). F NMR
3
3
1
C=C), 1136–1173 (C–F). H NMR spectrum (CDCl ),
3
spectrum (CDCl ): δ 91.17 ppm, s (CF ). Mass spec-
3 F 3
+·
δ, ppm: 2.63 s (3H, SCH ), 3.54 s (3H, NCH ), 6.55 s
3
3
trum, m/z (I , %): 224 (100) [M] , 209 (59) [M –
rel
1
9
+
+
+
(
1H, 5-H). F NMR spectrum (CDCl ): δ 89.91 ppm,
s (CF ). Mass spectrum, m/z (I , %): 224 (40) [M] ,
09 (6) [M – CH ] , 205 (7) [M – F] , 196 (1)
M – CO] , 191 (3) [M – HS] , 179 (100) [M – CHS] ,
3 F
CH ] , 205 (9) [M – F] , 191 (<1) [M – HS] , 178 (32)
3
+
·
+
+
3
rel
[M – CH S] , 138 (11) [M – NCS – C H ] , 109 (18)
2 2 4
[M – CH O – CH – CF ] , 69 (12) [CF ] , 68 (9)
C H NCO] , 45 (11) [CHS] .
2 2
+
+
+
+
2
[
1
[
3
3 3 3 3
+
+
+
+
+
[
+
+
38 (3) [M – NCS – C H ] , 69 (12) [CF ] , 68 (4)
2 4 3
4
-(Heptafluoropropyl)-6-methoxy-2-(methylsul-
+
+
C H NCO] , 45 (11) [CHS] . Found, %: C 37.66;
2 2
fanyl)pyrimidine (4b). Yield 16 mg (5%) (c), color-
H 3.13; N 12.35. C H F N OS. Calculated, %:
–1
7
7
3
2
less oil. IR spectrum (ATR), ν, cm : 1586, 1558
C 37.50; H 3.15; N 12.49.
1
(
C=N, C=C), 1123–1227 (C–F). H NMR spectrum
6
-(Heptafluoropropyl)-3-methyl-2-(methylsul-
fanyl)pyrimidin-4(3H)-one (3b). Yield 240 mg (74%)
c), white powder, mp 29–30°C. IR spectrum (ATR), ν,
(CDCl ), δ, ppm: 2.56 s (3H, SCH ), 4.03 s (3H,
3
3
19
OCH ), 6.72 s (1H, 5-H). F NMR spectrum (CDCl ),
3
3
(
δ , ppm: 36.22 m (2F, CF ), 45.51 m (2F, CF ), 82.35 t
F 2 2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019

7
90
KHUDINA et al.
(
(
2
[
3F, CF , J = 9.3 Hz). Mass spectrum, m/z (I , %): 324
filtered off, the filtrate was concentrated, and the
residue was recrystallized from acetonitrile (6a) or
ethanol–chloroform (1:2, 6b).
3
rel
+·
+
+
100) [M] , 309 (54) [M – CH ] , 305 (11) [M – F] ,
3
+
+
91 (<1) [M – HS] , 278 (33) [M – CH S] , 238 (18)
2
+
+
M – NCS – C H ] , 69 (33) [CF ] , 68 (24)
2 4 3
Potassium 1-methyl-6-oxo-4-(trifluoromethyl)-
+
[
C H NCO] , 45 (17) [CHS]. Found, %: C 33.49;
2
2
1
,6-dihydropyrimidin-2-olate (6a). Yield 153 mg
H 2.09; N 8.60. C H F N OS. Calculated, %: C 33.34;
9
7
7
2
(
66%), white powder, mp 364–365°C (decomp.). IR
H 2.18; N 8.64.
-Ethoxy-2-(ethylsulfanyl)-6-(trifluoromethyl)-
pyrimidine (4c). Yield 129 mg (51%) (c), colorless
oil. IR spectrum (ATR), ν, cm : 2985, 2934 (CH),
1
spectrum (CDCl ), δ, ppm: 1.41 t (6H, CH CH , J =
7
OCH , J = 7.2 Hz), 6.66 s (1H, 5-H). C NMR
spectrum (CDCl ), δ , ppm: 14.04 (CH ), 14.23 (CH ),
–1
spectrum (DR), ν, cm : 3152, 3097 (CH), 1668
4
(C=O), 1643, 1624, 1600, 1568 (C=N, C=C), 1107–
1
1207 (C–F). H NMR spectrum (DMSO-d
), δ, ppm:
), 5.47 s (1H, 5-H). F NMR spec-
): δ 92.37 ppm, s (CF ). Found, %:
. Calculated,
6
–
1
19
3.06 s (3H, NCH
trum (DMSO-d
C 30.89; H 1.75; N 12.01. C
%: C 31.04; H 1.74; N 12.06.
3
1
590, 1558 (C=N, C=C), 1101–1185 (C–F). H NMR
6
F
3
H F KN O
6 4 3 2 2
3
2
3
.2 Hz), 3.15 q (2H, SCH , J = 7.2 Hz), 4.47 q (2H,
2
1
3
2
Potassium 4-(heptafluoropropyl)-1-methyl-6-
oxo-1,6-dihydropyrimidin-2-olate (6b). Yield
242 mg (73%), white powder, mp 372–374°C
3
C
3
3
5
2
3
5.42 (SCH ), 63.42 (OCH ), 100.41 q (C , J =
2 2
6
–
1
.1 Hz), 120.33 q (CF , J = 274.7 Hz), 155.91 q (C ,
3
(decomp.). IR spectrum (DR), ν, cm : 3089, 2952
CH), 1654 (C=O), 1590, 1567 (C=N, C=C), 1116–
4
2
19
J = 35.5 Hz), 169.47 (C ), 173.56 (C ). F NMR spec-
trum (CDCl ): δ 91.15 ppm, s (CF ). Mass spectrum,
m/z (I , %): 252 (98) [M] , 233 (10) [M – F] , 223
(
1
3
F
3
1232 (C–F). H NMR spectrum (DMSO-d ), δ, ppm:
3.06 s (3H, NCH ), 5.47 s (1H, 5-H). C NMR spec-
trum (DMSO-d ), δ , ppm: 26.54 (NCH ), 92.94 t (C ,
6
+·
+
1
3
rel
3
+
+
5
(
[
[
[
68) [M – C H ] , 219 (23) [M – HS] , 191 (100)
2 5
+
6
C
3
+
M – C H S] , 138 (83) [M – NCS – C H ] , 109 (21)
2
5
4
8
J = 4.6 Hz), 108.67 t.sext (CF , J = 266, 37 Hz),
2
+
+
M – C H O – C H – CF ] , 69 (16) [CF ] , 68 (40)
C H NCO] , 45 (16) [CHS] . Found, %: C 42.62;
2
5
2
5
3
3
112.56 t.t (CF , J = 255.1, 28.9 Hz), 117.62 (CF , J =
2
3
+
+
4
2
2
287.5, 34.3 Hz), 153.08 t (C , J = 23.5 Hz), 158.88
(C ), 165.30 (C ). F NMR spectrum (DMSO-d ), δ ,
2
6
19
H 4.49; N 11.01. C H F N OS. Calculated, %:
9
11
3
2
6 F
C 42.85; H 4.40; N 11.11.
-Ethoxy-3-methyl-6-(trifluoromethyl)pyrimi-
din-4(3H)-one (5). A mixture of compound 3a
1 mmol) and potassium carbonate (414 mg, 3 mmol)
ppm: 36.77 m (2F, CF ), 46.02 m (2F, CF ), 82.64 t
2
2
(
3F, CF , J = 9 Hz). Found, %: C 28.72; H 1.43;
2
3
N 8.22. C H F KN O . Calculated, %: C 28.92;
8
4
7
2
2
H 1.21; N 8.43.
(
in anhydrous ethanol (15 mL) was refluxed for 3 h.
The precipitate was filtered off, the filtrate was con-
centrated, and the product was isolated by column
chromatography using hexane–ethyl acetate (4:1) as
eluent. Yield 71 mg (32%), colorless oil. IR spectrum
ACKNOWLEDGMENTS
This study was performed using the equipment of
the “Spectroscopy and Analysis of Organic Com-
pounds” joint center. Quantum chemical calculations
were carried out on a cluster supercomputer at the Ufa
Institute of Chemistry (Ufa Federal Research Center,
Russian Academy of Sciences).
–
1
(
1
DR), ν, cm : 3068, 2996 (CH), 1697 (C=O), 1556,
507 (C=N, C=C), 1071–1163 (C–F). H NMR spec-
1
trum (CDCl ), δ, ppm: 1.45 t (3H, CH CH , J =
3
2
3
7
7
.1 Hz), 3.44 s (3H, NCH ), 4.54 q (2H, OCH , J =
3 2
19
.1 Hz), 6.48 s (1H, 5-H). F NMR spectrum (CDCl ):
3
FUNDING
δ 89.72 ppm, s (CF ). Mass spectrum, m/z (I , %):
F
3
rel
+
·
+
+
2
1
22 (30) [M] , 207 (10 [M – CH ] , 203 (8) [M – F] ,
94 (100) [M – C H ] , 178 (23) [M – OC H ] , 166
3
This study was performed in the framework of state
assignment no. AAAA-A19-119011790132-7 and
under financial support by the Ministry of Science and
Higher Education of the Russian Federation (state
assignment no. AAAA-A17-117011910028-7).
+·
+
2
4
2
4
+
+
(
19) [M – COC H ] , 137 (59) [M – COC H – NCH ] ,
2 4 2 4 3
+
+
1
08 (13) [M – OC H – CF ,] , 69 (9) [CF ] , 68 (41)
2 5 3 3
+
[
C H NCO] . Found, %: C 42.97; H 4.03; N 12.44.
2 2
C H F N O . Calculated, %: C 43.25; H 4.08; N 12.61.
8
9
3
2
2
Uracil potassium salts 6a and 6b (general proce-
CONFLICT OF INTERESTS
dure). A mixture of compound 3a or 3b (1 mmol) and
potassium carbonate (414 mg, 3 mmol) in ethanol
The authors declare the absence of conflict of
interests.
(
15 mL) was refluxed for 3 h. The precipitate was
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019

ALKYLATION OF 6-POLYFLUOROALKYL-2-THIOURACILS WITH HALOALKANES
791
REFERENCES
17. Erkin, A.V. and Krutikov, V.I., Russ. J. Gen. Chem.,
2
007, vol. 77, p. 124. doi 10.1134/S1070363207010173
1
2
. Lagoja, I.M., Chem. Biodiversity, 2005, vol. 2, p. 1. doi
18. Senda, S. and Suzui, A., Chem. Pharm. Bull., 1958,
1
0.1002/cbdv.200490173
vol. 6, p. 479. doi 10.1248/cpb.6.479
19. Matsukawa, T. and Ohta, B., Yakugaku Zasshi, 1950,
vol. 70, p. 134; Chem. Abstr., 1950, vol. 44, p. 30180.
. Verma, A., Sahu, L., Chaudhary, N., Dutta, T.,
Dewangan, D., and Tripathi, D.K., Asian J. Biochem.
Pharm. Res., 2012, vol. 2, p. 1.
20. Lee, H.-J., Kim, D.-H., Kim, T.-K., Yoon, Y.-A.,
Sim, J.-Y., Cha, M.-H., Jung, E.-J., Ahn, K.-K., and
Lee, T.-A., Int. Patent Appl. no. WO 2012115478;
Chem. Abstr., 2012, vol. 157, no. 438379.
21. Westaway, S.M., Preston, A.G.S., Barker, M.D.,
Brown, F., Brown, J.A., Campbell, M., Chung, C.,
Drewes, G., Eagle, R., Garton, N., Gordon, L.,
Haslam, C., Hayhow, T.G., Humphreys, P.G., Joberty, G.,
Katso, R., Kruidenier, L., Leveridge, M., Pember-
ton, M., Rioja, I., Seal, G.A., Shipley, T., Singh, O.,
Suckling, C.J., Taylor, J., Thomas, P., Wilson, D.M.,
Lee, K., and Prinjha, R.K., J. Med. Chem., 2016,
vol. 59, p. 1370. doi 10.1021/acs.jmedchem.5b01538
3
4
. Choi, H.-J., Yu, S.-T., Lee, K.-I., Choi, J.-K.,
Chang, B.-Y., Kim, S.-Y., Ko, M.-H., Song, H.-O., and
Park, H., Exp. Parasitol., 2014, vol. 143, p. 24. doi
1
0.1016/j.exppara.2014.05.002
. Abdullah, M.E., Aboul-Enein, H.Y., Hassan, M.M.A.,
and Taha, S.A., Proc. Int. Symp. Appl. Technol. Ioniz.
Radiat., 1983, vol. 1, p. 531; Chem. Abstr., 1984,
vol. 100, p. 17232.
5. Attardo, G., Tripathy, S., and Gagnon, M., Int. Patent
Appl. no. WO2010132999.
6
. Gullpelli, K., Bhaskar, P., Muralikrishna, T., and
Brahmeshwari, G., Int. J. Pharm. Biol. Sci., 2014, vol. 4,
p. 59.
2
2. Dean, W.D. and Papadopoulos, E.P., J. Heterocycl.
Chem., 1982, vol. 19, p. 1117. doi 10.1002/
jhet.5570190527
7
. Lokwani, D., Azad, R., Sarkate, A., Reddanna, P., and
Shinde, D., Bioorg. Med. Chem., 2015, vol. 23, p. 4533.
doi 10.1016/j.bmc.2015.06.008
2
3. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scu-
seria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G.,
Barone, V., Mennucci, B., Petersson, G.A., Naka-
tsuji, H., Caricato, M., Li, X., Hratchian, H.P., Izmay-
lov, A.F., Bloino, J., Zheng, G., Sonnenberg, J.L.,
Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hase-
gawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O.,
Nakai, H., Vreven, T., Montgomery, J.A., Jr.,
Peralta, J.E., Ogliaro, F., Bearpark, M., Heyd, J.J.,
Brothers, E., Kudin, K.N., Staroverov, V.N., Koba-
yashi, R., Normand, J., Raghavachari, K., Rendell, A.,
Burant, J.C., Iyengar, S.S., Tomasi, J., Cossi, M.,
Rega, N., Millam, J.M., Klene, M., Knox, J.E.,
Cross, J.B., Bakken, V., Adamo, C., Jaramillo, J.,
Gomperts, R., Stratmann, R.E., Yazyev, O., Austin, A.J.,
Cammi, R., Pomelli, C., Ochterski, J.W., Martin, R.L.,
Morokuma, K., Zakrzewski, V.G., Voth, G.A., Sal-
vador, P., Dannenberg, J.J., Dapprich, S., Daniels, A.D.,
Farkas, Ö., Foresman, J.B., Ortiz, J.V., Cioslowski, J.,
and Fox, D.J. Gaussian 09, Revision C.01, Wallingford
CT: Gaussian, 2009.
8
. Nugent, R.A., Schlachter, S.T., Murphy, M.J.,
Cleek, G.J., Poel, T.J., Wishka, D.G., Graber, D.R.,
Yagi, Y., Keiser, B.J., Olmsted, R.A., Kopta, L.A.,
Swaney, S.M., Poppe, S.M., Morris, J., Tarpley, W.G.,
and Thomas, R.C., J. Med. Chem., 1998, vol. 41,
p. 3793. doi 10.1021/JM9800806
9
. Smart, B.E., J. Fluorine Chem., 2001, vol. 109, p. 3. doi
1
0.1016/S0022-1139(01)00375-X
1
0. Khudina, O.G., Ivanova, A.E., Burgart, Ya.V., Slepu-
khin, P.A., Saloutin, V.I., Chupakhin, O.N., and Krav-
chenko, M.A., Russ. Chem. Bull., Int. Ed., 2013, vol. 62,
p. 1060. doi 10.1007/s11172-013-0142-x
1
1. Ringom, R., Axen, E., Uppenberg, J., Lundback, T.,
Rondahld, L., and Barf, T., Bioorg. Med. Chem. Lett.,
004, vol. 14, p. 4449. doi 10.1016/j.bmcl.2004.06.058
2
1
2. Huang, T.H., Tu, H.Y., Aibibu, Z., Hou, C.J., and
Zhang, A.D., Arkivoc, 2011, part (ii), p. 1. doi 10.3998/
ark.5550190.0012.201
1
3. Khudina, O.G., Burgart, Ya.V., and Saloutin, V.I., Chem.
Heterocycl. Compd., 2014, vol. 50, p. 856. doi 10.1007/
s10593-014-1539-7
2
4. Tao, J.M., Perdew, J.P., Staroverov, V.N., and
Scuseria, G.E., Phys. Rev. Lett., 2003, vol. 91, article
no. 146401. doi 10.1103/PhysRevLett.91.146401
1
1
4. Bergmann, E.D., Cohen, S., and Shahak, I., J. Chem.
Soc., 1959, p. 3278. doi 10.1039/jr9590003278
25. McLean, A.D. and Chandler, G.S., J. Chem. Phys., 1980,
vol. 72, p. 5639. doi 10.1063/1.438980
26. Tomasi, J., Mennucci, B., and Cammi, R., Chem. Rev.,
5. Gershon, H., Grefig, A.T., and Scala, A.A., J. Hetero-
cycl. Chem., 1983, vol. 20, p. 219. doi 10.1002/
jhet.5570200145
2005, vol. 105, p. 2999. doi 10.1021/cr9904009
2
7. Miller, W.H., Dessert, A.M., and Anderson, G.W., J. Am.
Chem. Soc., 1948, vol. 70, p. 500. doi 10.1021/
ja01182a020
1
6. Bhabak, K.P. and Mugesh, G., Chem. Eur. J., 2010,
vol. 16, p. 1175. doi 10.1002/chem.200902145
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019