Desulfurization of 2-thioxo-1,2,3,4-tetrahydropyrimidin-4-ones with oxiranes and 2-haloacetonitriles

Article abstract of DOI:10.1007/s11178-005-0211-1

A procedure was developed for the synthesis of tetrahydropyrimidine-2,4- diones by desulfurization of 2-thioxo-1,2,3,4-tetrahydropyrimidin-4-ones with oxiranes or 2-haloacetonitriles in polar solvents in the presence of a base.

Full text of DOI:10.1007/s11178-005-0211-1

Russian Journal of Organic Chemistry, Vol. 41, No. 4, 2005, pp. 607–609. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 4, 2005,
pp. 617–619.
Original Russian Text Copyright © 2005 by Novakov, Orlinson, Navrotskii.
Desulfurization of 2-Thioxo-1,2,3,4-tetrahydropyrimidin-4-ones
with Oxiranes and 2-Haloacetonitriles
I. A. Novakov, B. S. Orlinson, and M. B. Navrotskii
Volgograd State Technical University, pr. Lenina 28, Volgograd, 400131 Russia
e-mail: phanchem@vstu.ru
Received July 5, 2003
Abstract—A procedure was developed for the synthesis of tetrahydropyrimidine-2,4-diones by desulfurization
of 2-thioxo-1,2,3,4-tetrahydropyrimidin-4-ones with oxiranes or 2-haloacetonitriles in polar solvents in the
presence of a base.
It is known that 2-thioxo-1,2,3,4-tetrahydropyrimi-
din-4-one derivatives differently react with different
alkylating agents. In most cases, the reaction gives the
corresponding 2-alkylsulfanylpyrimidin-6(1H)-ones or
2-alkylsulfanyl-1-alkylpyrimidin-4(1H)-ones, while
2-chloroacetic acid reacts with 2-thioxo-1,2,3,4-tetra-
hydropyrimidin-4-ones in an aqueous solution to
afford tetrahydropyrimidine-2,4-diones.
We found that 2-methyloxirane and 2-iodoaceto-
nitrile are also capable of effecting desulfurization of
2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one derivatives
with formation of 1,2,3,4-tetrahydropyrimidine-2,4-di-
ones (Scheme 1). The reactions were performed using
the following base–solvent systems (which are typic-
ally used for alkylation of 2-thioxo-1,2,3,4-tetrahydro-
pyrimidin-4-ones): K2CO3–DMFA, NaH–DMFA,
NaOMe–MeOH, KOH–EtOH, and NaOH–H2O. The
yield of the resulting pyrimidine-2,4-dione derivatives
was quantitative, regardless of the base used.
While studying desulfurization of 2-thioxo-1,2,3,4-
tetrahydropyrimidin-4-ones Ia–Ie we showed that
2-phenyloxirane and 2-ethyloxirane also equally effec-
tive in this reaction, and the corresponding 1,2,3,4-
tetrahydropyrimidine-2,4-diones IIa–IIe were formed
in quantitative yield. Presumably, the reason is that the
examined oxirane derivatives possess an endocyclic
methylene group which is not shielded with respect to
nucleophilic attack. Both protic polar solvents (H2O,
MeOH, EtOH) and aprotic dimethylformamide
ensured quantitative formation of pyrimidinediones
IIa–IIe. This suggests that the solvent does not parti-
cipate in the reaction with initially formed 2-[(2-hy-
droxyalkyl)sulfanyl]pyrimidinone and that oxirane acts
as source of oxygen.
Desulfurization of compounds Ia–Ie with 2-iodo-
acetonitrile (as well as with 2-bromo- and 2-chloro-
acetonitrile) resulted in quantitative formation of
pyrimidinediones IIa–IIe only when the reaction was
carried out in an alcoholic medium. The reaction in
DMF in the presence of K2CO3 was accompanied by
strong tarring. Treatment of Ia–Ie with 2-iodoaceto-
nitrile in aqueous sodium hydroxide afforded com-
pounds IIa–IIe in a poor yield, and the conversion of
initial 2-thioxopyrimidinones was not complete. These
data indicate that the process should be performed in
a protic solvent which is likely to promote cleavage of
the initially formed 2-(cyanomethylsulfanyl) deriva-
tive. The low yield of pyrimidine-2,4-diones in the
reaction in water may be due to heterogeneous con-
ditions and concurrent hydrolysis of 2-iodoacetonitrile.
It should be noted that the maximal yield of com-
pounds II in the reactions with both substituted
oxiranes and 2-haloacetonitriles was observed only
when the amount of base was equal to or greater than
equimolar. Reduction of the amount of base leads to
proportional decrease in the conversion (according to
the HPLC data). Therefore, the base acts as a reagent
rather than catalyst.
Scheme 1.
O
O
2-Methyloxirane or 2-iodo-
acetonitrile, base
R'
R'
NH
NH
R
N
H
S
R
N
H
O
Ia–Ie
IIa–IIe
R = R' = H (a); R = Me, R' = H (b); R = PhCH2, R' = H (c);
R = 2,6-F2C6H3CH2, R' = H (d); R = H, R' = Me (e).
1070-4280/05/4104-0607 © 2005 Pleiades Publishing, Inc.

NOVAKOV et al.
608
Scheme 2.
O
N
O
R'
R'
B–
NH
NH
R
SH
R
N
N
S
O
O
N
O
N
N
S
R'
R'
R'
HlgCH2CN
B–
H2O/AlkOH
NH
NH
NH
R
N
O
SCH2CN
R
R
O–
O
O
R''
R'
R'
NH
O–
R
N
S
R
N
O–
R''
R'' = Me, Et, Ph; B is a base; Hlg = Cl, Br, I.
Desulfurization of 2-thioxo-1,2,3,4-tetrahydropyri-
midin-4-ones with 2-haloacetonitriles and oxiranes
was not reported previously. On the other hand, the re-
action of sodium thiosulfate and thiourea with oxiranes
is known to give the corresponding thiiranes [4]. Here,
the source of sulfur is sodium thiosulfate or thiourea.
Presumably, the examined reactions of 2-thioxopyri-
midinones I follow an analogous mechanism. Unlike
compounds I, there is no need of deprotonating thio-
urea to ensure its nucleophilic attack on oxirane ring.
2-(2-hydroxyalkyl)- and 2-(cyanomethylsulfanyl)pyri-
midin-6(1H)-ones to undergo solvolysis (intra- or
intermolecular, respectively).
EXPERIMENTAL
The mass spectra (electron impact, 70 eV) were
recorded on a Varian MAT-111 spectrometer with
direct sample admission into the ion source. The
melting points were determined on a MelTemr 3.0
apparatus at a heating rate of 10 deg/min. HPLC
analysis was performed on a Waters ALC/GPC-244
chromatograph under the following conditions: com-
pound IId: 125×3-mm column, stationary phase
Inertsil ODS (5 µm), eluent MeCN–H2O (10:10, by
volume) + 5 ml of 1 N H2SO4; flow rate 0.1 ml/min,
UV detector with a diode matrix (λ 280 nm); com-
pounds IIa–IIc and IIe: 250×4.6-mm column, sta-
tionary phase Licrosphere RP8, eluent MeCN–MeOH
(67:33), flow rate 0.3 ml/min. The IR spectra were
obtained in KBr on a Perkin–Elmer 580 instrument.
TLC analysis was performed using Sorbfil plates;
eluent CH2Cl2–MeOH (19:1); spots were visualized
under UV light or by treatment with iodine vapor.
There are published data indicating that cyano-
methyl esters readily undergo hydrolysis [5]. There-
fore, we presumed that 2-thioxo-1,2,3,4-tetrahydro-
pyrimidin-4-one reacts with 2-iodoacetonitrile in the
presence of a base to give initially 2-(cyanomethyl-
sulfanyl)pyrimidin-6(1H)-one whose solvolysis leads
to formation of the corresponding pyrimidinedione
(Scheme 2).
Ethyl 2-bromoacetate and 2-bromo-1,1-dimethoxy-
ethane are known to react with 2-thioxo-1,2,3,4-tetra-
hydropyrimidin-4-ones to afford 2-(ethoxycarbonyl-
methylsulfanyl)pyrimidin-6(1H)-ones [6] and 2-(2,2-
dimethoxyethylsulfanyl)pyrimidin-6(1H)-ones [7],
respectively. Therefore, the only 2-haloacetic acid
derivatives capable of desulfurizing 2-thioxo-1,2,3,4-
tetrahydropyrimidin-4-ones are 2-haloacetic acids
themselves or the corresponding nitriles.
1,2,3,4-Tetrahydropyrimidine-2,4-diones IIa–IIe.
a. Compound Ia–Ie, 10 mmol, was dissolved on
heating under stirring in 11 ml of a 1 N aqueous solu-
tion of sodium hydroxide. The solution was cooled to
room temperatury, 11 mmol of 2-substituted oxirane
was added, and the mixture was stirred until initial
compound I disappeared (TLC, after acidification).
The mixture was neutralized with 1 N hydrochloric
Thus the observed desulfurization of 2-thioxo-
1,2,3,4-tetrahydropyrimidin-4-ones by the action of
oxiranes and 2-haloacetonitriles may be rationalized
in terms of a strong ability of the initially formed
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DESULFURIZATION OF 2-THIOXO-1,2,3,4-TETRAHYDROPYRIMIDIN-4-ONES
609
acid, and the precipitate was filtered off, washed with
water (25 ml), and dried. The yield of IIa–IIe was
almost quantitative.
acidification). The mixture was neutralized with 1 N
hydrochloric acid, and the precipitate was filtered off,
washed with 5 ml of methanol, and dried. The reaction
of Ia–Ie with 2-haloacetonitriles in ethanol in the
presence of KOH was carried out in a similar way.
Yield of IIa–IIe nearly quantitative.
1,2,3,4-Tetrahydropyrimidine-2,4-dione (IIa).
mp 335°C (decomp.) [8].
6-Methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione
(IIb). mp 300°C (decomp.) [8].
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6-(2,6-Difluorobenzyl)-1,2,3,4-tetrahydropyrimi-
dine-2,4-dione (IId). mp >300°C (decomp.; from
AcOH). IR spectrum: ν(C=O) 1660 cm–1. Mass spec-
trum, m/z (Irel, %): 238 (32) M+, 219 (0.1), 195 (0.8),
175 (14), 152 (8) 127 (27), 68 (100). Found, %:
C 55.42; H 3.48; F 15.90; N 11.71. M + 238.
C11H8F2N2O2. Calculated, %: C 55.47; H 3.49; F 15.95;
N 1 1.76. M 238.20.
5-Methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione
(IIe). mp >336°C (decomp.) [9].
b. A mixture of 5 mmol of compound Ia–Ie, 5 ml of
anhydrous DMF, and 0.69 g (5 mmol) of K2CO3 was
stirred for 45 min at 90–100°C. The mixture was then
cooled to 20°C, 5.5 mmol of 2-substituted oxirane was
added, and the mixture was stirred until initial com-
pound I disappeared (TLC). The mixture was diluted
with 100 ml of water and neutralized with 1 N hydro-
chloric acid, and the precipitate was filtered off,
washed with 25 ml of water on a filter, and dried. The
reaction of Ia–Ie with oxiranes in DMF in the presence
of NaH was carried out in a similar way. Yield of IIa–
IIf nearly quantitative.
6. Danel, K., Nielsen, C., and Pedersen E.B., Acta Chem.
Scand., 1997, vol. 51, p. 426.
c. Compound Ia–Ie, 5 mmol, was dissolved under
stirring in a solution of 0.32 g (6 mmol) of sodium
methoxide in 20 ml of methanol, 5.5 mmol of 2-halo-
acetonitrile was added, and the mixture was stirred
until initial compound I disappeared (TLC, after
7. Danel, K., Pedersen, E.B., and Nielsen, C., J. Med.
Chem., 1998, vol. 41, p. 191.
8. The Merck Index, N.J.: Merck & Co., 2001, 13th ed.
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