A convenient synthetic approach to derivatives of 5-phenylsulfonyl-2- thiouracil and its condensed analogs

Article abstract of DOI:10.1134/S1070363208060194

3-Amino-2-phenylsulfonylacrylonitrile, an available multicenter reagent, when treated successively with phenyl, ethyl, or allyl isothiocyanate and hydrochloric acid forms N³-substituted 5-phenylsulfonylthiouracils. Some of them were found to be suitable starting mateials for preparing of thiazoline and thiodiazolidine structures fused with the 4-pyrimidone system.

Full text of DOI:10.1134/S1070363208060194

ISSN 1070-3632, Russian Journal of General Chemistry, 2008, Vol. 78, No. 6, pp. 1210–1214. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © S.V. Slivchuk, V.S. Brovarets, B.S. Drach, 2008, published in Zhurnal Obshchei Khimii, 2008, Vol. 78, No. 6, pp. 982–986.
A Convenient Synthetic Approach to Derivatives
of 5-Phenylsulfonyl-2-Thiouracil and Its Condensed Analogs
S. V. Slivchuk, V. S. Brovarets, and B. S. Drach
Institute of Bioorganic and Petroleum Chemistry, National Academy of Sciences of Ukraine,
Murmanskaya ul. 1, Kiev-94, 02660 Ukraine
e-mail: drach@bpci.kiev.ua
Received December 25, 2007
Abstract—3-Amino-2-phenylsulfonylacrylonitrile, an available multicenter reagent, when treated successively
with phenyl, ethyl, or allyl isothiocyanate and hydrochloric acid forms N3-substituted 5-phenylsulfonyl-
thiouracils. Some of them were found to be suitable starting mateials for preparing of thiazoline and
thiodiazolidine structures fused with the 4-pyrimidone system.
DOI: 10.1134/S1070363208060194
Development of facile synthetic procedures for
preparing pyrimidine bases containing strong electron-
acceptor groups on the C5 atom presents significant
interest not only for investigations into specific
reactivity of such electron-deficient systems, but also
for preparing bioregulators of diverse action. In this
connection our research into transformations of 5-
nitropyrimidines [1] and functionalized 5-pyrimidyl-
phosphonium salts [2] over the past 15 years proved to
be important. Quite recently [3] we offered a
convenient synthetic approach to 5-arylsulfonyl-
substituted uracils and cytosines on the basis of enami-
nonitriles of the general formula RNHCH=C(CN)·
SO2Ar. In their turn, these compounds are easily
formed from the products of condensation of aryl-
sulfonylacetonitriles with triethoxymethane [4]. In the
present work we showed that the sequence of
transformations I → II → III → IV → V holds
promise as a route to previously unknown 5-phenyl-
sulfonylthiouracil derivatives, which significantly
extends the range of methods for preparing such
compounds [5–12]. As seen from the scheme, reagent
I is treated with phenyl, ethyl, or allyl isothiocyanate
in the presence of triethylamine, and cyclization
products II are heated with 10% HCl. Under these
conditions, N3-substituted 5-phenylsulfonylthiouracils
IV are formed in high yields (Table 1). Despite the
fact, that only three representatives of compounds IV
were prepared, the application field of the suggested
approach is undoubtedly wider, since many alkyl and
aryl isothiocyanates can evidently react with enamino-
nitrile I according to a [2+4]-cycloaddition scheme
characteristic of two model heterocumulenes, ethyl and
phenyl isothiocyanates.
Note that the use of allyl isothiocyanate in this
reaction allows one to introduce the allyl radical
specifically to the N3 center of the thiouracil system.
At the same time, to synthesize an S-allyl derivative of
3-phenyl-5-phenylsulfonylthiouracil, we used to
success the transformation IVa → V presented in the
scheme. Under the action of bromine or HCl,
substituted thiouracils containing S- and N-allyl groups
undergoexpected intramolecular cyclizations to form
substituted thiazoline and thiazolidine fragments fused
with the 4-pyrimidone system (structures VI–X. The
regioselectivity of such electrophilic cyclizations was
repeatedly discussed previously. Therefore, in con-
sidering the structure of compounds VI–VIII we took
account of publications concerning cyclizations of S-
allyl [13–15] and N-allyl [16] derivatives of
pyrimidine bases. Even though the mechanism of such
cyclizations is intricate [17, 18], their motive forces are
evident, because they are connected with the effect of
halogens, halogen chlorides, and some other
electrophilic agents on the electron density distribution
in the allyl group, which can lead to transition states
like A and favor cyclization (see scheme).
It is interesting that treatment of the reaction
product of N3-allyl-5-phenylsulfonylthiouracil with
bromine with triethylamine under ordinary conditions
gives a mixture of two condensed bases IX, X in a 1 : 1
1210

A CONVENIENT SYNTHETIC APPROACH TO DERIVATIVES
1211
NH
PhSO2
CN
R
PhSO2
PhSO2
CN
NHR
S
N
RN =C=S, Et3N
Et3N, Δ
N
H
N
H
S
NH2
I
IIа−IIc
IIIа−IIIc
H2O, HCl
O
N
R
S
(1) EtONa; (2)
R = Ph
Br
PhSO2
HCl, EtOH
R = All
N
H
H Cl
O
N
O
Ph
PhSO2
PhSO2
IVа−IVc
N
N
H
S
N
S
R = All
Br2, AcOH
V
А
2 Br2, CHCl3
HCl, EtOH
O
O
O
Ph
N
PhSO2
PhSO2
PhSO2
N
N
S
Br
+
N
+
N
+
N
S
Me
Br3−
Cl−
Br−
S
H
H
VII
VIII
Br
2 AcONa, Δ
2 Et3N, ~20o
VI
O
N
O
PhSO2
PhSO2
N
N
IX (~50%) +
S
N
S
Me
CH2
IX (>80%)
X (~50%)
R = Ph (a), Et (b), CH2=CHCH2 (c).
ratio. This mixture cannot be separated by crystal-
lization, and preparative synthesis of product IX is
better performed by dehydrobromination of compound
VI with sodium acetate. Isomeric pairs of condensed
bases similar to IX and X have already been described
[15].
Note in conclusion that the structure of all the
compounds presented in the scheme not only follows
from the procedure of their synthesis, but is also
consistent with their IR and 1H NMR spectra (Table 2).
The IR spectra of compounds III–IX lack absorption
bands in the range 2100–2300 cm–1, implying that the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 6 2008

1212
SLIVCHUK et al.
Table 1. Yields, constants, and elemental analyses of compounds III–IX
Yield,
%
mp, °С
Found, %
Calculated, %
S (Cl, Br)
Comp.
no.
Formula
(EtOH)
S (Cl, Br)
N
N
54
60
78
>300
>300
20.93
21.84
20.85
13.58
14.17
9.14
C13H13N3O2S2
C12H13N3O2S2
C13H12N2O3S2
20.86
21.71
20.80
13.67
14.23
9.08
IIIb
IIIc
IVb
251-253
79
86
71
95
63
80
244–246
213–215
178–180a (decomp.)
21.63
16.78
9.56
7.33
4.26
6.03
8.05
9.10
C12H12N2O3S2
21.64
16.68
9.45
7.29
3.98
5.98
8.12
9.14
IVc
V
C19H16N2O3S2
9.21 (44.56)
13.82 (34.44)
18.70 (10.30)
20.98
C19H16Br4N2O3S2
C13H12Br2N2O3S2
C13H13ClN2O3S2
C13H10N2O3S2
9.11(45.39)
13.70(34.13)
18.60(10.28)
20.93
VI
157–159
VII
VIII
IX
241–243
226–228
a Compound VI was not additionally purified.
Table 2. Spectral data for compounds III–IX
Comp.
IR spectrum, ν, cm–1
1H NMR spectrum, δ, ppm (DMSO-d6)
no.
1630 (C=NH), 3100–3300 (NHassoc
)
)
5.03–5.25 m (4Н, 2СН2), 5.78 m (1Н, СН), 7.59–7.73 m (3Н, С6Н3), 8.00–8.30 m (4Н,
NН, C6H2, C6–H)
1.18 t (3Н, СН3), 4.53 m 7.59–7.73 m (3Н, С6Н3), 8.00–8.10 m (4Н, NН, C6H2, C6–H)
IIIb
1625 (C=NH), 3050–3350 (NHassoc
IIIc
IVb
1675 (С=О), 3100–3350 (NHassoc
1670 (С=О), 3050–3350(NHassoc
)
4.77 m (2Н, СН2), 5.12 m (2Н, СН2), 5.75 m (1Н, СН), 7.56–7.91 m (5Н, С6Н5), 8.10 s
(1Н, C6–H), 13.43 br.s (1Н, NН)
1.12 t (3Н, СН2), 4.20 m (2Н, СН2), 7.56–8.00 m (5Н, С6Н5), 8.08 s (1Н, C6–H), 13.37
)
IVc
V
br.s (1Н, NН)
1700 (С=О), 3100–3600 (bands are 3.81 d (2Н, SСН2), 5.14 d, 5.31 d (2Н, СН2), 5.83 m (1Н, СН), 7.30–7.98 m (10Н,
absent)
2С6Н5), 8.63 s (1Н, C6–H)
1730 (С=О, band with a shoulder), 3.17 m (2Н, СН2), 4.01 m (2Н, СН2), 4.93 m (1Н, СН), 7.14–7.94 m (10Н, 2С6Н5),
VI
3100–3600 (bands are absent)
8.57 s (1Н, C5–H)
1705 (С=О), 3080 (NH)
3.91 m (2Н, СН2), 4.38 m (3Н, СН2, СН), 6.87 br.s (1Н, NН), 7.57–7.99 m (5Н, С6Н5),
8.47 s (1Н, C7–H)
VII
VIII
IX
1725 (С=О, band with a shoulder), 0.94 d (3Н, СН3), 3.60 d.d, 3.94 d.d (2Н, СН2), 3.67 m (1Н, СН), 7.07–7.49 m (5Н,
3200–3400 (NHassoc
С6Н5), 8.01 s (1Н, C7–H), 8.36 br.s (1Н, NН)
)
1685 (С=О), 3150–3600 (bands are 2.42 s (3Н, СН3), 7.58–8.01 m (6Н, 2С6Н5, C3–H), 8.70 s (1Н, C7–H)
absent)
Xa
–
5.06 s (2Н, СН2), 5.53 d (2Н, СН2), 7.58–8.02 (5Н, С6Н5), 8.56 s (1Н, C7–H)
a The 1H NMR spectrum of compound X is extracted from the spectrum of the mixture of compounds IX and X.
cyano group of reagent I is involved in cyclization just
on early stages of the process. Furthermore, the
carbonyl group of the 4-pyrimidone fragment in all the
thiouracil derivatives IV–IX is readily identified by IR
spectroscopy (νCO 1670–1730 cm–1). At the same time,
evidence for the similar nature of compounds IV–IX
Finally, the presence of the corresponding substituents
in the mononuclear (IV, V) and condensed (VI–X)
heterocyclic structures was also confirmed by means
of 1H NMR spectra (Table 2).
EXPERIMENTAL
1
is provided by the observation the H NMR spectra of
a narrow singlet signal at 8.0-8.7 ppm, assignable to
The IR spectra were recorded on a Specord M-80
spectrometer in KBr pellets. The H NMR spectra
the proton at the C6 center the 4-pyrimidone ring.
1
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 6 2008

A CONVENIENT SYNTHETIC APPROACH TO DERIVATIVES
1213
were taken on a Varian VXR-300 spectrometer in
DMSO-d6 against internal TMS. Compounds IIIa and
IVa were prepared by the procedure described in [3].
2-Methyl-5-oxo-6-phenylsulfonyl-2,3-dihydro-
5H-[1,3]thiazolo[3,2-a]pyrimidinium chloride (VIII).
Compound IVb, 0.002 mol, was suspended in 40 ml of
absolute ethanol, and anhydrous hydrogen chloride
was passed through the suspension over the course of
2 h with stirring under reflux. After cooling, the
precipitate that formed was filtered off, and compound
VIII was purified by crystallization.
3-Alkyl-4-imino-5-phenylsulfonyl-3,4-dihydro-
1H-pyrimidine-2(1H)-thiones (IIIb, IIIc). A mixture
of 0.0048 mol of 3-amino-2-phenylsulfonylacrylo-
nitrile (I) [4], 0.0053 mol of alkyl isothiocyanate, and
0.0053 mol of triethylamine was heated from 25°C to
95°C over the course of 10–15 min, kept at that tem-
perature for 15–20 min, and then diluted with 25 ml
of ethanol. The precipitate that formed was filtered off,
washed with 25 ml of acetone, and compounds IIIb
and IIIc were purified by crystallization.
2-Methyl-6-phenylsulfonyl-5H-[1,3]thiazolo[3,2-
a]-pyrimidin-5-one (IX). A mixture of 0.0013 mol of
compound VII and 0.0026 mol of anhydrous sodium
acetate was refluxed with stirring for 8 h. The
precipitate that formed was filtered off, washed with
water, and compound IX was purified by
crystallization.
3-Alkyl-2-thioxo-5-phenylsulfonyl-3,4-dihydro-
3H-pyrimidin-4-ones (IVb, IVc) were prepared by
acid hydrolysis of the corresponding imino compounds
by the procedure described in [3].
2-Methylene-6-phenylsulfonyl-2,3-dihydro-5H-
[1,3]thiazolo[3,2-a]pyrimidin-5-one (X). A solution
of 0.0013 mol of compound VII and 0.0026 mol of
triethylamine in 30 ml of acetonitrile was stirred at 20–
25°C for 10–12 h. The precipitate that formed was
filtered off, washed with water, dried, and crystallized
from ethanol to obtain a mixture of compounds IX and
X in a ~1 : 1 ratio (by 1H NMR). Attempted separation
of this mixture by crystallization failed.
2-Allylsulfanyl-1-phenyl-5-phenylsulfonylpyri-
midin-3H-4-one (V). To a solution of 0.003 mol of
sodium ethylate in 15 ml of absolute ethanol, 0.003 mol
of compound IVa was added, and the suspension
formed was stirred until the solid phase dissolved
completely. Allyl bromide, 0.004 mol, was added to
the solution, and the mixture was refluxed for 30 min
and then cooled. The precipitate formed was filtered
off, washed in succession with ethanol and water, and
compound V was purified by crystallization.
ACKNOWLEDGMENTS
The work was financially supported by the
Ukranian Science and Technology Center [project
3017(R)].
3-Bromomethyl-7-oxo-8-phenyl-6-phenylsulfo-
nyl-2,3,7,8-tetrahydro[1,3]thiazolo[3,2-a]pyrimidi-
nium tribromide (VI). To a solution of 0.0013 mol of
compound V in 25 ml of anhydrous chloroform a
solution of 0.0027 mol of bromine in 15 ml of
anhydrous chloroform was added under stirring and
cooling with ice. The reaction mixture was stirred at 0°C
for 20 min, the precipitate was filtered off, washed
with chloroform, and dried in an oil-pump vacuum at
30–40°C to obtain compound VI. The product was
analyzed without additional purification.
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