Halocyclization of 2-allyl(propargyl)sulfanyl-6-aminopyrimidin-4(3H)-ones

Article abstract of DOI:10.1134/S1070428017120235

The alkylation of 6-amino-2-thiouracil with allyl, methallyl, and propargyl halides in the presence of bases gave 2-[allyl(methallyl, propargyl)sulfanyl]-6-aminopyrimidin-4(3H)-ones which reacted with iodine and bromine to form fused [1,3]thiazolo[3,2-a]pyrimidinium systems. Their nitrosation with sodium nitrite in acid medium afforded 2-[allyl(propargyl)sulfanyl]-6-amino-5-nitrosopyrimidin-4(3H)-ones.

Full text of DOI:10.1134/S1070428017120235

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 12, pp. 1899–1902. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © D.G. Kim, K.Yu. Osheko, T.V. Frolova, 2017, published in Zhurnal Organicheskoi Khimii, 2017, Vol. 53, No. 12, pp. 1863–1866.
SHORT
COMMUNICATIONS
Halocyclization of 2-Allyl(propargyl)sulfanyl-
6
-aminopyrimidin-4(3H)-ones
D. G. Kim,* K. Yu. Osheko, and T. V. Frolova
South Ural State University, pr. imeni Lenina 76, Chelyabinsk, 454080 Russia
*
e-mail: kim_dg48@mail.ru
Received June 28, 2017
Abstract—The alkylation of 6-amino-2-thiouracil with allyl, methallyl, and propargyl halides in the presence
of bases gave 2-[allyl(methallyl, propargyl)sulfanyl]-6-aminopyrimidin-4(3H)-ones which reacted with iodine
and bromine to form fused [1,3]thiazolo[3,2-a]pyrimidinium systems. Their nitrosation with sodium nitrite in
acid medium afforded 2-[allyl(propargyl)sulfanyl]-6-amino-5-nitrosopyrimidin-4(3H)-ones.
DOI: 10.1134/S1070428017120235
It is known that [1,3]thiazolo[3,2-a]pyrimidine
derivatives obtained from 6-amino-2-thiouracil 1 ex-
hibit antibacterial, antimycotic, and antiviral activities
Allyl sulfide 2a reacted with iodine in acetic acid
to give 5-amino-3-(iodomethyl)-7-oxo-2,3,7,8-tetrahy-
dro[1,3]thiazolo[3,2-a]pyrimidin-4-ium iodide (3a)
(Scheme 2). The melting point of 3a coincided with
the melting point reported in [5] for the product
obtained by reaction of 2a with iodine in alcohol. The
[1–3]. Thiazolo[3,2-a]pyrimidines can be synthesized
by heterocyclization of S-alkenyl derivatives of 2-thio-
uracils by the action of electrophilic reagents [4–6].
There are contradictory published data [4, 5, 7] both on
the synthesis of 2-(allylsulfanyl)-6-aminopyrimidin-
1
positions of most signals in the H NMR spectra of
these compounds were also similar, except for the 6-H
proton. The latter resonated at δ 5.72 ppm rather than
at δ 6.99 ppm as given in [5], which is fairly surpris-
ing. In order to elucidate the observed inconsistency,
we studied analogous reaction of sulfide 2b with
iodine. We thus isolated 5-amino-3-(iodomethyl)-3-
methyl-7-oxo-2,3,7,8-tetrahydro[1,3]thiazolo[3,2-a]-
pyrimidin-4-ium iodide (3b) which displayed a signal
4
(3H)-one (2a) and 2-(methallylsulfanyl)-6-amino-
pyrimidin-4(3H)-one (2b) and on the reaction on allyl
sulfide 2a with halogens. Therefore, the goal of the
present work was to study in more detail the synthesis
of allyl sulfides 2a and 2b and 6-amino-2-(pro-
pargylsulfanyl)pyrimidin-4(3H)-one (2c) and their
reactions with electrophiles.
1
The reactions of thiouracil 1 with allyl bromide and
methallyl chloride were carried out in aqueous ethanol
in the presence of alkali. In both cases, we isolated
crystalline allyl sulfides 2a and 2b which were poorly
soluble in water. Slivka et al. [5] obtained compounds
at δ 5.83 ppm (6-H) in the H NMR spectrum (cf.
δ 6.16 ppm in [5]). Probably, the value δ 6.99 ppm
given in [5] was a misprint, and the correct value
should be δ 5.99 ppm. Iodide 3a was also synthesized
by us by reaction of 2a with iodine generated in situ. In
this case, allyl sulfide 2a was dissolved in hydriodic
acid, and hydrogen peroxide was added to the solution
(oxidative iodocyclization).
2
a and 2b as dark yellow oily substances readily
soluble in water. The structure of allyl sulfides 2a and
1
1
2
b was confirmed by H NMR spectra (no H NMR
1
data was given in [5]). The H NMR spectra of 2a and
b contained signals from protons of the allyl groups
2
Scheme 1.
and 5-H at δ 5.00 and 4.86 ppm, respectively. By
reaction of thiouracil 1 with propargyl bromide in
aqueous–alcoholic alkali we synthesized for the first
time propargyl sulfide 2c (Scheme 1) which showed in
the H NMR spectrum signals at δ 3.16 ppm due to
terminal acetylenic proton and at δ 5.04 ppm due to
O
O
RHlg
KOH, EtOH
NH
NH
H N
2
N
SH
H N
2
N
SR
1
1
2a–2c
5
-H of the pyrimidine ring.
R = CH
2
=CHCH
2
(a), CH
2
=C(Me)CH
2
(b), CH≡CCH
2
(c).
1
899

1
900
KIM et al.
Scheme 2.
H
H
O
N
(1) I , AcOH
(1) Br , AcOH
O
N
S
2
2
S
(
2) NaI, Me CO
(2) Me CO
2
2
I–
I
2a
Br–
Br
N
N
Br
NH2
NH2
3
a
4
The reaction of propargyl sulfide 2c with iodine
pyrimidin-4(3H)-ones 5a and 5c, respectively
(Scheme 4). The nitrosation of 6-amino-2-[methyl
(ethyl, benzyl)sulfanyl]pyrimidin-4(3H)-ones was re-
ported previously [11, 12].
afforded previously unknown 5-amino-3-(iodomethyli-
dene)-7-oxo-2,3,7,8-tetrahydro[1,3]thiazolo[3,2-a]py-
rimidin-4-ium iodide (3c) (Scheme 3). The 6-H proton
1
in 3c resonated in the H NMR spectrum at
δ 5.70 ppm, which is in agreement with the results
obtained for iodide 3a. We believe that the exocyclic
double bond in iodide 3c has E configuration, as in the
iodocyclization product of 6-methyl-2-(propargylsul-
fanyl)pyrimidin-4(3H)-one, whose structure was
Scheme 4.
O
ON
+
NaNO , H
NH
2
2
a, 2c
H N
2
N
SR
13
proved by C NMR [8].
5
a, 5c
Scheme 3.
1
The H NMR spectra of 5a and 5c contained signals
typical of allyl and propargyl substituents, but no
signal assignable to 5-H was present. The IR spectra of
these compounds displayed absorption bands at 1559
H
(
(
1) I2
2) NaI, Me CO
O
N
S
2
2
c
I–
N
–
1
and 1256–1253 cm due to vibrations of the N=O
group. Compounds 5a and 5c are colored blue, which
is characteristic of nitrosoarenes [13].
NH2
I
3
c
According to the data of [5], the reaction of 2a with
equiv of bromine produced 5-amino-3-(bromo-
methyl)-7-oxo-2,3,7,8-dihydro[1,3]thiazolo[3,2-a]py-
Thus, the reaction of 6-amino-2-thiouracil with
propargyl bromide gives 6-amino-2-(propargylsul-
fanyl)pyrimidin-4(3H)-one whose reaction with iodine
leads to fusion of 1,3-thiazole ring. The cyclization of
2-(allylsulfanyl)-6-aminopyrimidin-4(3H)-one to
thiazolopyrimidine system by the action of bromine is
accompanied by substitution of hydrogen in the py-
rimidine ring by bromine. 2-Allyl(propargyl)sulfanyl-
2
rimidinium bromide which showed a signal of 6-H at
1
δ 6.97 ppm in the H NMR spectrum; this value seems
doubtful.
We have found that the cyclization of 2a in the
reaction with bromine at the same reactant ratio is
accompanied by replacement of hydrogen in the
pyrimidine ring by bromine with formation of
6
-aminopyrimidin-4(3H)-ones undergo nitrosation at
the 5-position of the pyrimidine ring.
5
-amino-6-bromo-3-(bromomethyl)-7-oxo-2,3,7,8-tet-
rahydro[1,3]thiazolo[3,2-a]pyrimidin-4-ium bromide
4) (Scheme 2). In keeping with published data,
Reactions of 6-amino-2-thiouracil 1 with allyl
bromide, methallyl chloride, and propargyl
bromide (general procedure). 6-Amino-2-thiouracil 1,
1.61 g (10 mmol), was added to a solution of 0.56 g
(10 mmol) of potassium hydroxide in 15 mL of water,
a solution of 15 mmol of the corresponding halogen
derivative in 1 mL of ethanol was then added, and the
mixture was stirred for 1 h. The precipitate was filtered
off, washed with water, dried, and recrystallized from
propan-2-ol.
(
analogous cyclization and substitution were also
observed in the bromination of 2-(allylsulfanyl)-
6
2
-methylpyrimidin-4(3H)-one [9] and 1-allyl-6-amino-
-thiouracil [10].
The ease of hydrogen substitution in the pyrimidine
ring was confirmed by the fact that the reactions of
sulfides 2a and 2c with a soft electrophile, nitrous acid
generated in situ from sodium nitrite in acid medium,
resulted in nitrosation at the 5-position with formation
of 2-[allyl(propargyl)sulfanyl]-6-amino-5-nitroso-
6-Amino-2-(prop-2-en-1-ylsulfanyl)pyrimidin-
4(3H)-one (2a). Yield 1.592 g (87%), white powder,
–
1
mp 188–190°C. IR spectrum, ν, cm : 3474 v.s (NH ),
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 12 2017

HALOCYCLIZATION OF 2-ALLYL(PROPARGYL)SULFANYL-...
1901
3
1
1
287, 3198, 3091 (=CH ), 2712, 2364, 1656 s (C=O),
din-4-ium bromide (4). Allyl sulfide 2a, 0.183 g
(1 mmol), was added to a solution of 0.13 mL
(2.5 mmol) of bromine in 10 mL of acetic acid. After
24 h, the precipitate was filtered off and dissolved in
acetone, and the undissolved material was filtered off
2
620, 1571, 1543, 1454, 1373 (=CH), 1296, 1252,
1
227, 981, 977, 924 (=CH), 814, 609, 532. H NMR
spectrum, δ, ppm: 3.75 d (2H, SCH , J = 6.9 Hz),
2
5
5
6
.00 s (1H, 5-H), 5.10 d (1H, =CH , J = 16.9 Hz),
2
1
.33 d (1H, =CH , J = 10.0 Hz), 6.00 m (1H, =CH),
and dried. Yield 0.127 g (30%), mp >310°C. H NMR
2
.49 s (2H, NH2).
spectrum, δ, ppm: 3.60 d.d (2H, SCH ), 4.00 m (2H,
2
6
-Amino-2-(2-methylprop-2-en-1-ylsulfanyl)py-
CH
(2H, NH
Br
Compounds 5a and 5c (general procedure).
Sodium nitrite, 15 mmol, was added to a solution of
mmol of sulfide 2a or 2c in acetic acid, and the
2
Br), 5.25 m (1H, NCH, J = 8.99 Hz), 8.57 br.s
). Found, %: C 19.96; H 1.95; N 9.98.
OS. Calculated, %: C 19.93; H 1.91; N 9.96.
rimidin-4(3H)-one (2b). Yield 1.576 g (80%), white
powder, mp 264–266°C. H NMR spectrum, δ, ppm:
.76 s (3H, CH ), 3.78 s (2H, SCH ), 4.84 s (1H,
CH ), 4.92 s (1H, =CH ), 5.04 s (1H, 5-H), 6.47 s
2
1
C
H
N
3 3
7
8
1
=
(
3 2
2 2
2H, NH2).
-Amino-2-(prop-2-yn-1-ylsulfanyl)pyrimidin-
(3H)-one (2c). Yield 1.574 g (87%), white powder,
1
6
mixture was stirred for 2 h. The solvent was evaporat-
ed, and the residue was washed with water.
4
–
1
mp 206–208°C. IR spectrum, ν, cm : 3456 v.s (NH ),
271 v.s (≡C–H), 2122 (C≡C), 1672 s (C=O), 1612,
571, 1543, 1454, 1385, 1365 (≡CH), 1300, 1236,
191, 981, 916, 819, 710, 686 (≡CH), 593, 536, 463,
47. H NMR spectrum, δ, ppm: 3.16 t (1H, ≡CH, J =
.6 Hz), 3.92 d (2H, SCH , J = 2.6 Hz), 5.04 s
1H, 5-H), 6.55 s (2H, NH ). Found, %: C 46.34;
H 3.94; N 23.23. C H N OS. Calculated, %: C 46.39;
H 3.89; N 23.19.
2
6
-Amino-5-nitroso-2-(prop-2-en-1-ylsulfanyl)py-
3
1
1
4
2
(
rimidin-4(3H)-one (5a). Yield 0.091 g (43%), green–
blue powder, mp 173°C (decomp.). IR spectrum, ν,
–1
cm : 3303 s (NH ), 3158, 3060, 2898, v.s 1692
1
2
(
C=O), 1620, 1559 (N=O), 1506, 1462, 1389 (=CH),
2
1
8
312, 1256 (N=O), 1175, 1118, 1037, 993, 965 (=CH),
60, 823, 787, 714, 678, 653, 569, 544, 492, 455.
2
7
7
3
1
H NMR spectrum, δ, ppm: 3.84 s (2H, SCH , J =
2
6
.9 Hz), 5.13–5.39 d.d (2H, =CH , J = 9.8, 17.0 Hz),
2
5
-Amino-3-(iodomethyl)-7-oxo-2,3,7,8-tetrahy-
5
.92 m (1H, =CH), 11.17 s and 11.25 s (2H, NH2).
dro[1,3]thiazolo[3,2-a]pyrimidin-4-ium iodide (3a).
a. Allyl sulfide 2a, 0.183 g (1 mmol), was added to
a solution of 0.508 g (2 mmol) of iodine in 10 mL of
acetic acid. After 24 h, the solvent was evaporated, the
residue was dissolved in acetone and treated with
sodium iodide, and the precipitate was filtered off.
Yield 0.197 g (45%), mp 178–179°C (decomp.);
Found, %: C 39.65; H 3.79; N 26.44. C H N O S.
Calculated, %: C 39.61; H 3.80; N 26.40.
7
8
4
2
6
-Amino-5-nitroso-2-(prop-2-yn-1-ylsulfanyl)py-
rimidin-4(3H)-one (5c). Yield 0.160 g (76%), blue
powder, mp 181–183°C (decomp.). IR spectrum, ν,
–
1
cm : 3280 (NH ), 3222 s (≡C–H), 3075, 2973, 2100
2
1
(
(
(
C≡C), v.s 1696 (C=O), 1628, 1624, 1616, 1559
N=O), 1506, 1495, 1465, 1456, 1437, 1420, 1384 br
≡CH), 1314, 1272, 1253 (N=O), 1181, 1125, 1026,
published data [5]: mp 177–178°C. H NMR spectrum,
δ, ppm: 3.50–4.01 d.d (2H, SCH ), 3.62 m (2H, CH I),
2
2
5
8
.25 m (1H, NCH, J = 8.99 Hz), 5.72 s (1H, 6-H),
.59–8.63 br.s (2H, NH2).
9
6
68, 854, 807, 785, 754, 725, 708, 693 (≡CH), 668,
65, 650, 630, 575, 547, 491, 468, 418. H NMR spec-
1
b. Allyl sulfide 2a, 0.183 g (1 mmol), was dissolved
trum, δ, ppm: 3.29 s (1H, ≡CH), 4.07 s (2H, SCH2),
.13 s (1H, NH), 11.24 s and 12.77 s (2H, NH ).
in 5 mL of hydriodic acid, and 0.2 mL of 30% hy-
drogen peroxide was added. After 24 h, the precipitate
was filtered off and dissolved in acetone, sodium
iodide was added to the solution, and the precipitate
was filtered off. Yield 0.257 g (59%).
9
2
Found, %: C 39.97; H 2.86; N 26.69. C H N O S.
7
6
4
2
Calculated, %: C 39.99; H 2.88; N 26.65.
1
The H NMR spectra were recorded on a Bruker
DRX-400 spectrometer at 400 MHz using DMSO-d6
(
E)-5-Amino-3-(iodomethylidene)-7-oxo-2,3,7,8-
as solvent and tetramethylsilane as internal standard.
The IR spectra were recorded on a Bruker Tensor 27
spectrometer with Fourier transform.
tetrahydro[1,3]thiazolo[3,2-a]pyrimidin-4-ium
iodide (3c). a. Yield 0.222 g (51%), mp 184–186°C.
H NMR spectrum, δ, ppm: 4.34 s (2H, SCH ), 5.70 s
1
2
(
%
%
1H, 6-H), 7.21 s (1H, CHI), 8.51 s (2H, NH ). Found,
: C 19.30; H 1.60; N 9.67. C H I N OS. Calculated,
7 7 2 3
2
This study was performed under financial support
by the government of the Russian Federation
: C 19.33; H 1.62; N 9.66.
-Amino-6-bromo-3-(bromomethyl)-3-methyl-
-oxo-2,3,7,8-tetrahydro[1,3]thiazolo[3,2-a]pyrimi-
(
Resolution no. 211, Mar 16, 2013; contract
5
no. 02.A03.21.0011) and in the framework of state
assignment no. 4.9665.2017/8.9.
7
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1
902
KIM et al.
6. Kim, D.G. and Shmygarev, V.I., Chem. Heterocycl.
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