Synthesis of new derivatives of 5-alkyl-6-(2,6-dihalobenzyl)-2- (methylsulfanyl)pyrimidin-4(3H)-one and the features of their oxidation

Article abstract of DOI:10.1134/S1070428010110151

The synthesis and features of the regioselective S-monomethylation of new 5-alkyl-6-(arylmethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones were investigated, and also the character of the oxidative degradation of these compounds when treated with the syste

Full text of DOI:10.1134/S1070428010110151

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 11, pp. 1691−1694. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © I.A. Novakov, B.S. Orlinson, M.B. Navrotskii, A.S. Eremiichuk, L.L. Brunilina, E.A. Gordeeva, E.N. Gerasimov, 2010, published in
Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 11, pp. 1684−1687.
Synthesis of New Derivatives
of 5-Alkyl-6-(2,6-dihalobenzyl)-2-(methylsulfanyl)pyrimidin-
4(3H)-one and the Features of Their Oxidation
I. A. Novakov, B. S. Orlinson, M. B. Navrotskii, A. S. Eremiichuk,
L. L. Brunilina, E. A. Gordeeva, and E. N. Gerasimov
Volgograd State Technical University, Volgograd, 400131 Russia
e-mail: phanchem@vstu.ru
Received March 12, 2009
Abstract—The synthesis and features of the regioselective S-monomethylation of new 5-alkyl-6-(arylmethyl)-
2-thioxo-2,3-dihydropyrimidin-4(1H)-ones were investigated, and also the character of the oxidative degradation
of these compounds when treated with the system H2O2–AcOH.
DOI: 10.1134/S1070428010110151
Many derivatives of 6-(arylmethyl)-2-(methylsulfanyl) products of 3-oxoesters with thiourea decreased at the
pyrimidin-4(3H)-one are the key intermediates in the
growth and branching of the alkyl substituent in the
synthesis of highly active antiviral drugs [1–4]. In this position 2 of the 3-oxoester molecule. Evidently this is
connection we synthesized new derivatives of 5-alkyl- due both to the steric influence of the alkyl group and to
6-(2,6-dichlorobenzyl)-2-(methylsulfanyl)pyrimidin- its positive inductive effect (reducing the CH-acidity of
4(3H)-one and 5-alkyl-6-(2-fluoro-6-chlorobenzyl)-2- the 3-oxoester).
(methylsulfanyl)pyrimidin-4(3H)-one and studied certain
feature of their chemical behavior (Scheme 1).
It was also shown that the reaction of the obtained
2-thioxo-2,3-dihydropyrimidin-4(1H)-one derivatives
We established that the yield of the condensation with methyl iodide in 96% ethanol in the presence of
Scheme 1.
O
R'
COOEt
CN
Cl
(1) (H2N)2CS,
(1) R'CHBrCOOEt,
Zn, THF
(2) HCl_H2O
R'
NH
KOEt, EtOH
(2) AcOH_H2O
R
O
N
S
R
R
Cl
H
Cl
Ia_Ic, IIa_IIc
O
IIIa_IIIc, IVa_IVc
R'
O
NH
(1) MeI, KOH, EtOH
(2) AcOH_H2O
(1) MeI, KOH, EtOH
(2) AcOH_H2O
R
NH
N
SMe
R
Cl
N
H
S
Cl
IIId, IVd
Va_Vd, VIa_VId
R = F (I, IV, VI), Cl (II, III, V); R' = Me (a), Et (b), i-Pr (c), H (d).
1691

NOVAKOV et al.
1692
KOH proceeded relatively regioselectively giving virtu-
ally exclusively the products of the S-monomethylation
even at the fivefold excess of the alkylating agent. The
similar reaction carried out in anhydrous DMF in the
presence of K2CO3 always resulted in complex mixtures
of polyalkylated products. Thus in the reaction occurring
in a protic solvent the 4-(arylmethyl)-6-oxo-1,6-dihydro-
2-pyrimidinethiolate anion is surrounded with a tight
solvate shell due to the existence of the hydrogen bonds.
The destruction of this solvate shell evidently requires
considerable energy consumption, therefore the reaction
with methyl iodide proceeds prevailingly with the most
nucleophilic tautomeric form, 4-(arylmethyl)-6-oxo-
1,6-dihydro-2-pyrimidinethiolate anion. In the reaction
in DMF medium the anion is surrounded with less tight
solvate shell than in the case of lower alcohols, it is rela-
tively weak, and the methyl iodide reacts both with the
more nucleophilic 4-(arylmethyl)-6-oxo-1,6-dihydro-2-
pyrimidinethiolate anion and with the other tautomeric
forms of this anion where the negative charge is delocal-
ized predominantly on one of the nitrogen atoms or on the
oxygen atom. The high reactivity of the methyl iodide in
this case compensates the difference in the nucleophilic-
ity of these anions.
The data obtained allow a conclusion that
the regioselectivity of the methylation of the
2-thioxo-2,3-dihydropyrimidin-4(1H)-one derivatives
depends to a high degree on the chemical character of the
solvent, and the corresponding products are so prone to
the solvolysis that it results in their hydrolytic cleavage
in the reaction mixture.
EXPERIMENTAL
1H NMR spectra were registered on a spectrometer
Varian Mercury 300 BB at the operating frequency
300.73 MHz from solutions of compounds in DMSO-d6,
internal reference HMDS. Mass spectra were measured on
a GC-MS instrument Varian MAT-111 in the mode of the
direct admission of the sample into the ion source, ion-
izing electrons energy 70eV. Melting points were deter-
mined on Fisher–Johns heating block (Cole Palmer) at the
heating rate 10 deg/min. The homogeneity of compounds
obtained was proved by TLC on Alugram Nano-SIL
G/UV254 plates, development under UV irradiation.
Ethyl 3-oxo-4-(2-fluoro-6-chlorophenyl)-2-ethyl-
butanoate (Ib). To a mixture of 140 ml of anhydrous
THF and 12.8 g (0.196 mg-at) of zinc turnings was added
several drops of ethyl 2-bromobutanoate, the mixture was
boiled at stirring till the appearance of green color, 5.53 g
(34.89 mmol) of 2-(2-fluoro-6-chlorophenyl)acetonitrile
was charged, and dropwise was added 31.8 g (24 ml,
163.0 mmol) ethyl 2-bromobutanoate. The mixture was
boiled at stirring for another 30 min, the solution was
decanted, and THF was distilled off at a reduced pressure.
To the residue 250 ml of toluene and 90 ml of 3 N HCl was
poured, the mixture was stirred for 1.5 h at room tempera-
ture, the organic phase was separated, washed with water
till neutral washings, dried with MgSO4, concentrated
at a reduces pressure, and the product was distilled in a
We investigated the reaction of compounds VIa, VIb,
and VId with hydrogen peroxide in acetic acid aiming at
the probable preparation of the corresponding sulfones.
In this case in contrast to the other 2-(alkylsulfanyl)-
4(3H)-pyrimidinones the oxidation of the substances
under study with hydrogen peroxide in acetic acid did
not allow the isolation of sulfones. The only separated
reaction products were the corresponding uracils.
The probable reason of this phenomenon is the high
mobility of the methylsulfonyl group and consequently
the easy hydrolysis of the obtained sulfone (addition–
elimination mechanism).
Scheme 2.
O
O
O
R
R
R
NH
SMe
NH
NH
_
H2O2 AcOH
Δ
O
N
N
O
N
S
F
H
H2O
H2O
F
Cl
O
Me
F
Cl
Cl
VIIa, VIIb, VIId
VIa, VIb, VId
R = Me (a), Et (b), H (d).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 11 2010

SYNTHESIS OF NEW DERIVATIVES OF 5-ALKYL-6-(2,6-DIHALOBENZYL)-
1693
vacuum. Yield 9.35 g (81%), bp 135–146°C (1 mm Hg).
Found, %: C 59.04; H 5.22. [M]+ 286. C14H16ClFO3.
Calculated, %: C 58.64; H 5.62. M 286.73.
compound IIa. Yield 79%, mp 268–270°C (96% ethanol)
{258–260°C (96% ethanol) [5]}.
5-Ethyl-2-thioxo-6-(2,6-dichlorobenzyl)-2,3-di-
hydropyrimidin-4(1H)-one (IIIb) was obtained from
compound IIb. Yield 81%, mp 272–274°C (acetonitrile)
{270–271°C (96% ethanol) [1]}.
Compounds Ia, Ic, IIa–IIc were similarly prepared.
Ethyl 2-methyl-3-oxo-4-(2-fluoro-6-chlorophenyl)-
butanoate (Ia) was obtained using ethyl 2-bromo-pro-
panoate. Yield 78%, bp 125–128°C (1 mm Hg). Found,
%: C 57.04; H 5.12. [M]+ 272. C13H14ClFO3. Calculated,
%: C 57.26; H 5.17. M 272.7.
2-Thioxo-6-(2,6-dichlorobenzyl)-2,3-dihydro-
pyrimidin-4(1H)-one (IIId) was obtained by procedure
[6]. Yield 84%, mp 318–321°C (acetic acid).
Ethyl 2-isopropyl-3-oxo-4-(2-fluoro-6-chloro-phe-
nyl)butanoate (Ic) was obtained using ethyl 2-bromo-3-
methylbutanoate. Yield 63%, bp 147–157°C (1 mm Hg),
mp 50–51.5°C (hexane). Found, %: C 60.04; H 5.89.
[M]+ 300. C15H18ClFO3. Calculated, %: C 59.90; H 6.03.
M 300.7.
5-Methyl-2-thioxo-6-(2-fluoro-6-chlorobenzyl)-2,3-
dihydropyrimidin-4(1H)-one (IVa) was obtained from
compound Ia. Yield 84%, mp 253°C (decomp., 96%
ethanol) {253–254°C (96% ethanol) [1]}.
5-Ethyl-2-thioxo-6-(2-fluoro-6-chlorobenzyl)-2,3-
dihydropyrimidin-4(1H)-one (IVb) was obtained from
compound Ib. Yield 31%, mp 228–230°C (acetonitrile)
{228–230°C (acetonitrile) [1]}.
Ethyl 2-methyl-3-oxo-4-(2,6-dichlorophenyl)bu-
tanoate (IIa) was obtained from 2-(2,6-dichlorophenyl)
acetonitrile and ethyl 2-bromopropanoate. Yield 78%,
bp 143–150°C (0.6 mm Hg), mp 98–99°C (hexane)
{98–99°C (hexane) [5]}.
5-Isopropyl-2-thioxo-6-(2-fluoro-6-chloro-benzyl)-
2,3-dihydropyrimidin-4(1H)-one (IVc) was obtained
from compound Ic. Yield 32%, mp 240–242°C (aceto-
nitrile) {240–242°C (96% ethanol) [1]}.
Ethyl 3-oxo-4-(2,6-dichlorophenyl)-2-ethylbu-
tanoate (IIb) was obtained from 2-(2,6-dichlorophenyl)
acetonitrile and ethyl 2-bromobutanoate. Yield 65%, bp
148–153°C (0.5 mm Hg). Found, %: C 55.04; H 5.22.
[M]+ 303. C14H16Cl2O3. Calculated, %: C 55.46; H 5.32.
M 303.2.
2-Thioxo-6-(2-fluoro-6-chlorobenzyl)-2,3-dihydro-
pyrimidin-4(1H)-one (IVd) was obtained by procedure
[6]. Yield 78%, mp 268–270.5°C (acetic acid).
2-(Methylsulfanyl)-6-(2,6-dichlorobenzyl)-5-ethyl-
pyrimidin-4(3H)-one (Vb). To a solution of 84.8 mg
(1.4 mmol) of KOH in 25 ml of 96% ethanol was added
400 mg (1.27 mmol) of compound IIIb, the mixture was
stirred till dissolution, and 0.4 ml (6.35 mmol) of methyl
iodide was added, and then the mixture was stirred for
another 1 h. Then it was diluted with 70 ml of water,
acidified with acetic acid till pH 5, the precipitate was
filtered off, dried till constant weight, and recrystallized.
Yield 276 mg (66%), mp 246–249°C (96% ethanol–
DMF). Found, %: C 51.05; H 4.22; N 8.81. [M]+ 329.
C14H14Cl2N2OS. Calculated, %: C 51.07; H 4.29; N 8.51.
M 329.2.
Ethyl 2-isopropyl-3-oxo-4-(2,6-dichlorophenyl)bu-
tanoate (IIc) was obtained from 2-(2,6-dichlorophenyl)
acetonitrile and ethyl 2-bromo-3-methylpropanoate. Yield
62%, bp 158–164°C (0.6 mm Hg), mp 66–68°C (hexane).
Found, %: C 56.41; H 5.62. [M]+ 317. C15H18Cl2O3.
Calculated, %: C 56.80; H 5.72. M 317.2.
5-Isopropyl-2-thioxo-6-(2,6-dichlorobenzyl)-2,3-
dihydropyrimidin-4(1H)-one (IIIc). Amixture of 3.4 g
(10.7 mmol) of compound IIc, 5.4 g (64.1 mmol) of
potassium ethoxide, and 3.3 g (43.4 mmol) of thiourea
in anhydrous ethanol was boiled for 96 h, the solvent
was removed in a vacuum, the residue was dissolved in
water and filtered. The filtrate was acidified with acetic
acid to pH 5–6, the separated precipitate was filtered off,
washed with 10 ml of 96% ethanol, 30 ml of ether, dried,
and recrystallized. Yield 1.1 g (31%), mp 266.5–267.5°C
(acetonitrile) {262–264°C (96% ethanol) [1]}.
Compounds Va, Vc, Vd, VIa–VId were similarly
obtained.
5-Methyl-2-(methylsulfanyl)-6-(2,6-dichloro-
benzyl)pyrimidin-4(3H)-one (Va) was obtained from
compound IIIa. Yield 43%, mp 262–264°C (96% etha-
nol–DMF) {260–261°C (benzene–cyclohexane) [5]}.
Compounds IIIa, IIIb, IVa–IVd were similarly
obtained.
2-(Methylsulfanyl)-6-(2,6-dichlorobenzyl)-5-
isopropylpyrimidin-4(3H)-one (Vc) was obtained from
compound IIIc. Yield 50%, mp 247–248°C (toluene).
Found, %: C 52.00; H 4.81; N 8.50. [M]+ 343. C15H16Cl-
5-Methyl-2-thioxo-6-(2,6-dichlorobenzyl)-2,3-
dihydropyrimidin-4(1H)-one (IIIa) was obtained from
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 11 2010

NOVAKOV et al.
1694
2N2OS. Calculated, %: C 52.48; H 4.70; N 8.16. M 343.3.
1H NMR spectrum, δ, ppm: 1.69 s (3H, CH3), 3.68 s (2H,
CH2), 7.24 m (3H, CH), 10.73 br.s (1H, NH), 10.97 br.s
(1H, NH). Found, %: C 52.01; H 3.20; N 11.00. [M]+
254. C11H8ClFN2O2. Calculated, %: C 51.88; H 3.17;
N 11.00. M 254.6.
2-(Methylsulfanyl)-6-(2,6-dichlorobenzyl)-pyrim-
idin-4(3H)-one (Vd) was obtained analogously from
compound IIId. Yield 65%, mp 238–241°C (96% etha-
nol–DMF) {237–238°C (benzene) [5]}.
Compounds VIIa, VIIb were similarly obtained.
5-Methyl-2-(methylsulfanyl)-6-(2-fluoro-6-
chlorobenzyl)pyrimidin-4(3H)-one (VIa) was ob-
tained from compound IVa. Yield 62%, mp 241°C
5-Methyl-6-(2-fluoro-6-chlorobenzyl)pyrimidin-
2,4(1H,3H)-dione (VIIa) was obtained from compound
VIa. Yield 18%, mp >300°C (acetone–toluene). 1H NMR
spectrum, δ, ppm: 3.75 s (2H, CH2), 4.50 s (1H, CH),
7.27 m (2H, CH), 7.37 s (1H, CH), 10.99 br.s (1H, NH),
11.13 br.s (1H, NH). Found, %: C 54.04; H 4.10; N 10.08.
[M]+ 268. C12H10ClFN2O2. Calculated, %: C 53.65;
H 3.75; N 10.43. M 268.7.
1
(96% ethanol–DMF). H NMR spectrum, δ, ppm:
2.12 s (3H, CH3), 2.13 s (3H, CH3), 3.99 s (2H, CH2),
6.91 m (1H, CH), 7.09 m (2H, CH), 11.68 s (1H,
NH). Found, %: C 52.04; H 4.22; N 8.99. [M]+ 298.
C13H12ClFN2OS. Calculated, %: C 52.26; H 4.05;
N 9.38. M 298.8.
6-(2-Fluoro-6-chlorobenzyl)-5-ethylpyrimidin-
2,4(1H,3H)-dione (VIIb) was obtained from compound
Vb. Yield 48%, mp 271–272°C (acetone–toluene).
1H NMR spectrum, δ, ppm: 0.47 t (3H, CH3, J 8 Hz),
2.05 m (2H, CH2), 3.88 s (1H, CH), 7.20 m (1H, CH),
7.40 m (2H, CH), 10.72 br.s (1H, NH), 10.99 br.s (1H,
NH). Found, %: C 55.04; H 4.22; N 10.01. [M]+ 282.
C13H12ClFN2O2. Calculated, %: C 55.23; H 4.28; N 9.91.
M 282.7.
2-(Methylsulfanyl)-6-(2-fluoro-6-chlorobenzyl)-
5-ethylpyrimidin-4(3H)-one (VIb) was obtained
from compound IVb. Yield 75%, mp 209–211°C (96%
ethanol–DMF). 1H NMR spectrum, δ, ppm: 1.01 t
(3H, CH3, J 8.33 Hz), 1.09 s (2H, CH2), 2.00 s (3H,
CH3), 3.98 s (2H, CH2), 7.14 m (1H, CH), 7.28 m (2H,
CH), 12.49 s (1H, NH). Found, %: C 54.04; H 4.56;
N 9.07. [M]+ 312. C14H14ClFN2OS. Calculated, %:
C 53.76; H 4.51; N 8.96. M 312.8.
2-(Methylsulfanyl)-6-(2-fluoro-6-chlorobenzyl)-5-
isopropylpyrimidin-4(3H)-one (Vc) was obtained from
compound IVc. Yield 55%, mp 227–228°C (toluene).
Found, %: C 55.52; H 5.02; N 9.00. [M]+ 326. C15H16ClF-
N2OS. Calculated, %: C 55.12; H 4.94; N 8.57. M 326.8.
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2-(Methylsulfanyl)-6-(2-fluoro-6-chlorobenzyl)py-
rimidin-4(3H)-one (VId) was obtained from compound
IVd. Yield 60%, mp 217–219.5°C (96% ethanol–DMF).
1H NMR spectrum, δ, ppm: 2.30 s (3H, CH3), 3.90 s
(2H, CH2), 5.70 s (1H, CH), 7.20 m (1H, CH), 7.30 m
(2H, CH). Found, %: C 51.04; H 3.54; N 9.90. [M]+
284. C12H10ClFN2OS. Calculated, %: C 50.62; H 3.54;
N 9.84. M 284.7.
6-(2-Fluoro-6-chlorobenzyl)pyrimidin-2,4(1H,3H)-
dione (VIId). A mixture of 10 ml of AcOH, 0.9 ml
(38.7 mmol) of 30% H2O2, and 0.411 g (1.43 mmol) of
compound IVd was heated for 7 h at 75°C. Then the
volume of the reaction mixture was filled with water to
100 ml, and 6 h later the precipitate formed was filtered
off, recrystallized, and dried to the constant weight.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 11 2010