Synthesis and heterocyclization of 2-{[2-(4-bromophenyl)-2-oxoethyl]sulfanyl}pyrimidin-4(3H)-ones

Article abstract of DOI:10.1134/S1070428016010188

Alkylation of sodium 4(5)-alkyl-6-oxo-1,6-dihydropyrimidine-2-thiolates with 2-bromo-1-(4-bromophenyl)ethan-1-one afforded 2-{[2-(4-bromophenyl)-2-oxoethyl]sulfanyl}pyrimidin-4(3H)-ones. Analogous reaction with sodium 4-trifluoromethyl-6-oxo-1,6-dihydropyrimidine-2-thiolate gave a mixture of 2-{[2-(4-bromophenyl)-2-oxoethyl]sulfanyl}-4-(trifluoromethyl)pyrimidin-4(3H)-one and its intramolecular cyclization product, 3-(4-bromophenyl)-3-hydroxy-7-trifluoromethyl-2,3-dihydro[1,3]thiazolo[3,2-a]-pyrimidin-5-one.

Full text of DOI:10.1134/S1070428016010188

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 1, pp. 96–98. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © T.V. Frolova, D.G. Kim, V.V. Sharutin, E.N. Shal’kova, 2016, published in Zhurnal Organicheskoi Khimii, 2016, Vol. 52, No. 1,
pp. 103–105.
Synthesis and Heterocyclization of 2-{[2-(4-Bromophenyl)-
2-oxoethyl]sulfanyl}pyrimidin-4(3H)-ones
T. V. Frolova, D. G. Kim, V. V. Sharutin, and E. N. Shal’kova
South Ural State University, pr. Lenina 76, Chelyabinsk, 454071 Russia
e-mail: chemitash@gmail.com
Received October 19, 2015
Abstract—Alkylation of sodium 4(5)-alkyl-6-oxo-1,6-dihydropyrimidine-2-thiolates with 2-bromo-1-(4-
bromophenyl)ethan-1-one afforded 2-{[2-(4-bromophenyl)-2-oxoethyl]sulfanyl}pyrimidin-4(3H)-ones. Analo-
gous reaction with sodium 4-trifluoromethyl-6-oxo-1,6-dihydropyrimidine-2-thiolate gave a mixture of
2-{[2-(4-bromophenyl)-2-oxoethyl]sulfanyl}-4-(trifluoromethyl)pyrimidin-4(3H)-one and its intramolecular
cyclization product, 3-(4-bromophenyl)-3-hydroxy-7-trifluoromethyl-2,3-dihydro[1,3]thiazolo[3,2-a]-
pyrimidin-5-one.
DOI: 10.1134/S1070428016010188
Compounds containing a pyrimidine ring, in partic-
ular thiouracil derivatives, exhibit a broad spectrum of
biological activity [1, 2]. Among pyrimidine deriva-
tives, fused pyrimidines are of considerably greater
interest than monocyclic compounds from the view-
point of biological activity. A particular place is
occupied by thiazolopyrimidines which were shown to
possess fungicidal [3], anticonvulsant, antidiabetic,
anti-inflammatory, and analgesic properties [4], as well
as to act as efficient calcium channel blockers [5].
Unlike compounds 1a and 1b, the reaction of
4-trifluoromethyl-substituted derivative 1c with
2-bromo-1-(4-bromophenyl)ethan-1-one was accom-
panied by intramolecular cyclization of the alkylation
product, 2-{[2-(4-bromophenyl)-2-oxoethyl]sulfanyl}-
6-(trifluoromethyl)pyrimidin-4(3H)-one (2c), with
formation of 3-(4-bromophenyl)-3-hydroxy-7-tri-
fluoromethyl-2,3-dihydro[1,3]thiazolo[3,2-a]pyrimi-
din-5-one (3). According to the 1H NMR data, the ratio
2c:3 was 0.4:1. The observed difference in the reac-
tion directions may be rationalized by strong electron-
withdrawing effect of the trifluoromethyl group, which
enhances the NH acidity of 2c and facilitates its
A convenient procedure for the preparation of
thiazolopyrimidinones is based on intramolecular cy-
clization of 2-[(2-oxoethyl)sulfanyl]pyrimidin-4(3H)-
ones by the action of sulfuric acid [6]. The authors [6]
presumed that the heterocyclization involved the N3
rather than N1 atom on the basis of only 1H NMR data.
1
cyclization. Compound 3 displayed in the H NMR
spectrum signals from aromatic protons, a singlet at
δ 5.78 ppm from the OH proton, and two one-proton
doublets at δ 3.45–3.93 ppm from the SCH2 group.
In this work we studied the reaction of 2-bromo-1-
(4-bromophenyl)ethan-1-one with sodium 6-oxo-1,6-
dihydropyrimidine-2-thiolates 1a–1c prepared by con-
densation of thiourea with 1,3-dicarbonyl compounds
[7]. The alkylation of 1a and 1b gave 2-{[2-(4-bromo-
phenyl)-2-oxoethyl]sulfanyl}pyrimidin-4(3H)-ones 2a
and 2b (Scheme 1). The product structure was con-
Treatment of mixture 2c/3 with concentrated sul-
furic acid afforded 90% of 3-(4-bromophenyl)-7-tri-
fluoromethyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one
(4c). Proton in position 2 of 4c (thiazole ring) resonat-
ed in the 1H NMR spectrum as a singlet at δ 7.57 ppm.
The regioselectivity of the cyclization of 2c, which
involved exclusively the N3 atom, was confirmed by
X-ray analysis of thiazolopyrimidinone 4c (Fig. 1).
1
firmed by their H NMR spectra which contained
a singlet at δ 4.71 (2a) and 4.66 ppm (2b) due to the
SCH2 protons and aromatic proton signals in the region
δ 7.75–8.00 ppm. In the IR spectra of 2a and 2b
we observed absorption bands in the region 1658–
1695 cm–1, corresponding to stretching vibrations of
two carbonyl groups.
The thiazolopyrimidine system in molecule 4c is
planar, and the bromophenyl group is turned through
a dihedral angle of 50° with respect to that plane.
Packing of molecules 4c in crystal involves three short
contacts, two of which are formed between the sulfur
96

SYNTHESIS AND HETEROCYCLIZATION OF 2-{[2-(4-BROMOPHENYL)-...
97
Scheme 1.
O
N
O
N
O
N
C6H4Br-4
OH
C6H4Br-4
R'
R'
O
S
C6H4Br-4
Br
+
+
NH
NH
N
O
S
R
SNa
R
F3C
1a–1c
2a–2c
3
O
N
N
O
C6H4Br-4
C6H4Br-4
Br
H2SO4
Br2
R = CF3, R' = H
R'
Br
N
S
S
R
F3C
N
4a–4c
5
R = Me, R′ = H (a), Et (b); R = CF3, R′ = H (c).
and fluorine atoms (S···F 3.174 Å), and the third
contact is formed between aromatic hydrogen atoms of
different benzene rings (3.709 Å). Short contacts
between the fluorine atoms of different molecules
(2.669 Å) arrange stacks of molecular layers along the
c crystallographic axis (Fig. 2).
[8] and SAINT-Plus [9]. The structure was solved by
the direct method and refined by the least-squares
procedure in anisotropic approximation for non-hydro-
gen atoms using SHELXL/PC [10]. The complete
tables of atom coordinates, bond lengths, and bond
angles were deposited to the Cambridge Crystallo-
graphic Data Centre (entry no. CCDC 1013415).
Treatment of sulfides 2a and 2b with sulfuric acid
gave 3-(4-bromophenyl)-5H-[1,3]thiazolo[3,2-a]py-
rimidin-5-ones 4a and 4b. Unlike initial sulfides 2a
and 2b, compounds 4a and 4b showed in the IR
spectra only one carbonyl stretching band at 1686 and
1692 cm–1, respectively.
Compounds 2a–2c and 3 (general procedure).
Compound 1a–1c, 0.01 mol, was dissolved in 10 mL
of DMF, 2.78 g (0.01 mol) of p-bromophenacyl
bromide was added, and the mixture was stirred for
C6
S1
C5
Insofar as compound 4c may be regarded as an aro-
matic system with free positions 2 and 6, it was
interesting to find out which position is more reactive
toward electrophiles. For this purpose, compound 4c
was subjected to bromination with bromine in chloro-
N2
C2
C7
C8
C13
C9
N1
C4
F1
C10
C11
C1
F3
1
Br1
form on cooling. According to the H NMR data, the
O1
F2
C3
product was 2,6-dibromo-3-(4-bromophenyl)-7-tri-
fluoromethyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one
(5) (Scheme 1).
C12
Fig. 1. Structure of the molecule of 3-(4-bromophenyl)-7-
trifluoromethyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (4c)
according to the X-ray diffraction data.
EXPERIMENTAL
The IR spectra were recorded on a Varian 800 FT-
IR Scimitar Series spectrometer. The H NMR spectra
1
2.669
were measured from solutions in DMSO-d6 on
a Bruker DRX-400 spectrometer (400 MHz) using
tetramethylsilane as internal standard. The elemental
analyses were obtained on a Carlo Erba CHNS-O EA
1108 analyzer.
3.709
3.174
3.174
The X-ray diffraction data for compound 4c were
acquired with a Bruker D8 QUEST automated four-
circle diffractometer (Mo Kα radiation, λ 0.71073 Å,
graphite monochromator). The data were collected and
edited, the unit cell parameters were refined, and
a correction for absorption was applied using SMART
Fig. 2. Crystal packing of 3-(4-bromophenyl)-7-trifluoro-
methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (4c) accord-
ing to the X-ray diffraction data.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 1 2016

FROLOVA et al.
98
2 h. The mixture was then diluted with 35 mL of water,
and the precipitate was filtered off.
7.22 Hz), 7.32 s (1H, 2-H), 7.34 d (2H, Harom, J =
8.47 Hz), 7.56 d (2H, Harom, J = 8.46 Hz). Found, %:
C 51.51; H 3.78; N 8.12. C15H13BrN2OS. Calculated,
%: C 51.57; H 3.72; N 8.02.
2-{[2-(4-Bromophenyl)-2-oxoethyl]sulfanyl}-6-
methylpyrimidin-4(3H)-one (2a). Yield 2.27 g (67%),
mp 160°C. IR spectrum, ν, cm–1: 1695, 1661 (C=O).
1H NMR spectrum, δ, ppm: 1.95 s (3H, CH3), 4.71 s
(2H, SCH2), 5.96 s (1H, 5-H), 7.79 d (2H, Harom, J =
8.34 Hz), 7.98 d (2H, Harom, J = 8.35 Hz). Found, %:
C 46.16; H 3.12; N 8.31. C13H11BrN2O2S. Calculated,
%: C 46.01; H 3.24; N 8.25.
3-(4-Bromophenyl)-7-trifluoromethyl-5H-[1,3]-
thiazolo[3,2-a]pyrimidin-5-one (4c). Yield 0.337 g
(90%), mp 140°C. IR spectrum: ν 1692 cm–1 (C=O).
1H NMR spectrum, δ, ppm: 6.67 s (1H, 6-H), 7.41 d
(2H, Harom, J = 8.46 Hz), 7.57 s (1H, 2-H), 7.61 d (2H,
H
arom, J = 8.47 Hz). Found, %: C 41.57; H 1.58;
N 7.51. C13H6BrF3N2OS. Calculated, %: C 41.60;
H 1.61; N 7.46.
2-{[2-(4-Bromophenyl)-2-oxoethyl]sulfanyl}-
5-ethyl-6-methylpyrimidin-4(3H)-one (2b). Yield
2.27 g (62%), mp 184°C. IR spectrum, ν, cm–1: 1684,
1638 (C=O). H NMR spectrum, δ, ppm: 0.93 t (3H,
CH3CH2, J = 7.30 Hz), 1.93 s (3H, CH3), 2.29 q (2H,
CH2CH3, J = 7.02 Hz), 4.66 s (2H, SCH2), 7.79 d (2H,
2,6-Dibromo-3-(4-bromophenyl)-7-trifluoro-
methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (5).
A solution of 0.1 mL (0.001 mol) of bromine in 5 mL
of CHCl3 was added on cooling to 0.271 g (0.001 mol)
of compound 4c in 10 mL of CHCl3. After 24 h, the
mixture was evaporated, and the residue was washed
with 5 mL of ethanol. Yield 0.265 g (51%), mp 178°C.
1H NMR spectrum, δ, ppm: 7.41 d (2H, Harom, J =
8.47 Hz), 7.64 d (2H, Harom, J = 8.52 Hz). Found, %:
C 29.32; H 0.65; N 5.29. C13H4Br3F3N2OS. Calculated,
%: C 29.26; H 0.75; N 5.25.
1
Harom, J = 8.47 Hz), 7.97 d (2H, Harom, J = 8.42 Hz).
Found, %: C 48.99; H 4.15; N 7.63. C15H15BrN2O2S.
Calculated, %: C 49.04; H 4.08; N 7.62.
2-{[2-(4-Bromophenyl)-2-oxoethyl]sulfanyl}-6-
(trifluoromethyl)pyrimidin-4(3H)-one (2c). 1H NMR
spectrum, δ, ppm: 4.64 s (2H, SCH2), 6.53 s (1H, 5-H),
7.66 d (2H, Harom, J = 8.73 Hz), 7.88 d (2H, Harom
,
J = 8.69 Hz).
REFERENCES
3-(4-Bromophenyl)-3-hydroxy-7-trifluoro-
methyl-2,3-dihydro[1,3]thiazolo[3,2-a]pyrimidin-5-
one (3). 1H NMR spectrum, δ, ppm: 3.45 d and 3.93 d
(1H each, SCH2, J = 11.73 Hz), 5.78 s (1H, OH),
6.54 s (1H, 5-H), 7.24 d (2H, Harom, J = 8.78 Hz),
7.56 d (2H, Harom, J = 8.80 Hz).
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of 1 mmol of compound 2a–2c and 10 mL of sulfuric
acid was left to stand for 24 h at room temperature.
The mixture was poured into cold water and neutral-
ized with aqueous sodium hydroxide, and the precip-
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3-(4-Bromophenyl)-7-methyl-5H-[1,3]thiazolo-
[3,2-a]pyrimidin-5-one (4a). Yield 0.176 g (57%),
mp 110°C. IR spectrum: ν 1686 cm–1 (C=O). 1H NMR
spectrum, δ, ppm: 2.28 s (3H, CH3), 6.06 s (1H, 6-H),
7.65 d (2H, Harom, J = 8.66 Hz), 7.69 s (1H, 2-H),
7.75 d (2H, Harom, J = 8.49 Hz). Found, %: C 48.54;
H 2.86; N 8.65. C13H9BrN2OS. Calculated, %:
C 48.59; H 2.80; N 8.72.
3-(4-Bromophenyl)-6-ethyl-7-methyl-5H-[1,3]-
thiazolo[3,2-a]pyrimidin-5-one (4b). Yield 0.235 g
(70%), mp 120°C. IR spectrum: ν 1692 cm–1 (C=O).
1H NMR spectrum, δ, ppm: 0.93 t (3H, CH2CH3, J =
7.40 Hz), 2.32 s (3H, CH3), 2.41 q (2H, CH2CH3, J =
10. Bruker SHELXTL/PC. Versions 5.10. An Integrated
System for Solving, Refining and Displaying Crystal
Structures From Diffraction Data, Madison, Wisconsin,
USA: Bruker AXS, 1998.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 1 2016