Synthesis of [1,3]Thiazolo[2,3-i]purinium Systems

Article abstract of DOI:10.1134/S1070428018090233

The alkylation of purine-6-thiol with methallyl chloride and propargyl bromide in aqueous alcohol in the presence of alkali gave 6-[methallyl(propargyl)sulfanyl]purines which reacted with iodine and bromine to afford fused [1,3]thiazolo[2,3-i]purinium sys

Full text of DOI:10.1134/S1070428018090233

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 9, pp. 1406–1410. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © K.Yu. Osheko, D.G. Kim, O.S. El’tsov, T.S. Shtukina, 2018, published in Zhurnal Organicheskoi Khimii, 2018, Vol. 54, No. 9,
pp. 1390–1394.
Synthesis of [1,3]Thiazolo[2,3-i]purinium Systems
K. Yu. Oshekoa,* D. G. Kima, O. S. El’tsovb, and T. S. Shtukinab
a South Ural State University, pr. imeni Lenina 76, Chelyabinsk, 454080 Russia
*e-mail: osheko_kseniya@mail.ru
b Yeltsin Ural Federal University, ul. Mira 19, Yekaterinburg, 620002 Russia
Received February 28, 2018
Abstract—The alkylation of purine-6-thiol with methallyl chloride and propargyl bromide in aqueous alcohol
in the presence of alkali gave 6-[methallyl(propargyl)sulfanyl]purines which reacted with iodine and bromine
to afford fused [1,3]thiazolo[2,3-i]purinium systems.
DOI: 10.1134/S1070428018090233
Derivatives of purine-6-thiol (1) exhibit antitumor
and immunotropic activity, and they can be used for
the treatment of toxoplasmosis [1–5]. There are a few
published examples of synthesis of [1,3]thiazolo-
[2,3-i]purinium systems. One method is based on
heterocyclization of 6-(allylsulfanyl)purine by the
action of electrophilic agents [6, 7]. Other methods for
the preparation of analogous tricyclic systems include
reactions of purine 1 derivatives with 1,2-dibromo-
ethane, 2-bromocyclohexanone, and 2-(chloromethyl)-
oxirane [8–10].
thesize sulfide 2a by alkylation of purine 1 with
propargyl bromide, and sulfide 2b, by alkylation of 1
with methallyl chloride in aqueous alcohol in the pres-
ence of potassium hydroxide (Scheme 1). Compound
2a was synthesized previously by reaction of 1 with
propargyl bromide in liquid ammonia in the presence
of sodium amide [11].
When the reaction was carried out in boiling DMF
in the presence of potassium carbonate, methallyl sul-
fide 2b underwent partial isomerization to 6-[(2-meth-
ylpropen-1-yl)sulfanyl]purine (2c) (Scheme 2). The
1H NMR spectrum of 2c displayed two methyl proton
singlets at δ 1.85 and 1.95 ppm and a signal at
δ 6.80 ppm due to the SCH= proton.
Herein we describe the reactions of 6-(propargyl-
sulfanyl)purine (2a) and 6-(methallylsulfanyl)purine
(2b) with halogens with the goal of obtaining new
fused thiazolopurinium systems.
Scheme 2.
The alkylation of purine 1 with allyl bromide was
carried out in HMPA and in water in the presence of
potassium hydroxide [6, 7]. We were the first to syn-
H2C
S
Me
H
H
N
Me
S
Me
K2CO3
H
N
Scheme 1.
N
N
S
SH
N
H
N
H
N
N
N
N
N
N
N
2b
2c
N
N
N
H
The mass spectrum of 2a contained the molecular
ion peak [M]+ with a relative intensity of 17%, and the
base peak was that of propargyl cation with m/z 39
(Scheme 3). In the mass spectrum of 2b, the molecular
ion peak [M]+ had an intensity of 8%, while the maxi-
mum intensity peak (m/z 191) belonged to thiazolo-
purinium system resulting from elimination of methyl
radical (Scheme 4). In addition, the ion peak with
1
SK
SR
H
N
H
N
N
RHlg
N
KOH
N
N
N
N
2a, 2b
R = CH≡CCH2 (a), CH2=C(Me)CH2 (b).
1406

SYNTHESIS OF [1,3]THIAZOLO[2,3-i]PURINIUM SYSTEMS
1407
Scheme 3.
N
N
H
N
H
N
H
N
N
+·
·
–HCN
–CH≡
CCH2S
HC
N
N
N
S
N
N
N
CH
H
N
m/z 119
m/z 92
N
N
H2C
·
CH
–C5H3N4S
m/z 39
Scheme 4.
H2C
S
N
S
H
N
H
N
Me
N
N
+·
·
–C2H2
–Me
N
N
Me
S
CH2
N
m/z 191
m/z 165
CH2
H2C
H
N
·
–C5H3N4S
N
Me
m/z 55
N
N
H
N
N
·
–H2C=C(Me)CH2S
N
N
m/z 119
m/z 173 had a high intensity. This ion arises from
elimination of HS· radical via allyl group migration
from the sulfur atom to the N7 atom of the purine
system (pathway a) or through the formation of
pyrrolopurinium cation (pathway b; Scheme 5). We
believe that pathway b is more probable, as follows
from the fairly high intensity of that peak (26%),
which is typical of analogous stable systems.
The fragmentation pattern of sulfide 2c is similar to
the fragmentation of 2b, but the peak intensities are
different. For instance, the molecular ion peak of 2c has
an intensity of 90%, presumably due to higher stability
Scheme 5.
+·
Me
S
CH2
+·
+·
CH2
Me
Me
CH2
Me
a
S
N
SH
N
N
H
N
N
N
N
N
N
N
N
N
N
N
N
N
m/z 173
b
Me
Me
Me
S
N
S
SH
·
H
H
N
H
N
H
N
·
·
Me
N
·
N
N
N
N
–SH
N
N
N
N
N
N
N
m/z 173
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018

OSHEKO et al.
1408
Scheme 6.
S
8
7
Br
9
Br–
H
N
Me2CO
10
N6
1
3
N
4
N
S
Hlg
H
N
Hlg3
4
Hlg2
N
2a
S
N
N
I
I–
H
N
3, 5
NaI, Me2CO
N
N
N
6
3, Hlg = Br; 5, Hlg = I.
of the structure with conjugated double bond. The base
peak in the mass spectrum of 2c, as well as in the
spectrum of 2b, is that with m/z 191 [M – CH3]+. The
ion peaks with m/z 119 and 92 typical of compounds
2a–2c were assigned, respectively, to purinium cation
resulting from cleavage of the C6–S bond and 5-cyano-
imidazolium cation resulting from elimination of
hydrogen cyanide.
Propargyl sulfide 2a reacted with 2 equiv of
bromine in acetic acid to produce orange crystals of
(7E)-7-bromomethylidene-7,8-dihydro-3H-[1,3]thia-
zolo[2,3-i]purin-6-ium tribromide (3) which was con-
verted to colorless (7E)-7-bromomethylidene-7,8-dihy-
dro-3H-[1,3]thiazolo[2,3-i]purin-6-ium bromide (4) by
the action of acetone (Scheme 6). The reaction of 2a
with 2 equiv of iodine afforded (7E)-7-iodomethyli-
dene-7,8-dihydro-3H-[1,3]thiazolo[2,3-i]purinium tri-
iodide (5) as dark powder. Treatment of the latter with
sodium iodide in acetone gave light yellow
(7E)-7-iodomethylidene-7,8-dihydro-3H-[1,3]thiazolo-
[2,3-i]purinium iodide (6). When the reactions of 2a
with iodine and bromine were carried out using equi-
molar amounts of the reactants, the conversion of 2a
was incomplete, and the yield of the corresponding
trihalides did not exceed 50%.
tion. Therefore, we resorted to two-dimensional
1
1H–13C HSQC and HMBC and H–1H NOESY tech-
niques and found that the product of the reaction of 2b
with iodine after treatment of the reaction mixture with
sodium iodide in acetone was E-isomeric 7-iodo-
methylidene[1,3]thiazolo[2,3-i]purin-6-ium iodide (6)
having an exocyclic double bond. Characteristic
signals in the 1H and 13C NMR spectra of 6 were those
of the exocyclic =CHI group: the proton signal was
displaced downfield (δ 8.12 ppm), and the carbon
signal appeared in a strong field (δC 75.47 ppm) due to
effect of heavy iodine atom. The configuration of the
exocyclic double bond was determined on the basis of
the 2D NOESY data. The CHI proton displayed cou-
pling with proton on C5 of the thiazolopurine system,
which is possible only for the E configuration of the
1
double bond. Complete assignment of the H and
13C signals of 6 was done by analysis of the 2D 1H–13C
HSQC and HMBC spectra. Because of overlap by the
solvent signal, the CH2 chemical shift was determined
from the C–H direct coupling cross peak. The most
1
informative cross-peaks in the 2D H–13C HMBC
spectrum of 6 were the following: 2-H/C9a, 2-H/C3a,
8-H/C9a, 8-H/C7, 8-H/C10, 5-H/C9a, 5-H/C3a, 5-H/C7.
The reaction of 2b with iodine at a molar ratio of
1:2 in acetic acid afforded 7-(iodomethyl)-7-methyl-
7,8-dihydro-1H-[1,3]thiazolo[2,3-i]purin-6-ium tri-
iodide (7) as a dark solid which separated from the
reaction mixture. By treatment of 7 with sodium iodide
Theoretically, the reactions of compound 2a with
halogens may lead to compounds with both endo- and
1
exocyclic double bond. The H and 13C NMR data
were insufficient for unambiguous structure determina-
Scheme 7.
Br–
Br
I
I
S
S
S
H
N
H
N
H
N
Br2
I2
I3–
I–
2b
N
N
N
Me
Me
Me
N
N
N
N
N
N
9
7
8
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018

SYNTHESIS OF [1,3]THIAZOLO[2,3-i]PURINIUM SYSTEMS
1409
in acetone we obtained 7-(iodomethyl)-7-methyl-7,8-
dihydro-1H-[1,3]thiazolo[2,3-i]purin-6-ium iodide (8)
(Scheme 7). Compound 2b reacted with an equimolar
amount of bromine to give 7-(bromomethyl)-7-methyl-
7,8-dihydro-1H-[1,3]thiazolo[2,3-i]purin-6-ium iodide
=CH2), 8.46 s (1H, 8-H), 8.70 s (1H, 2-H). Mass spec-
trum, m/z (Irel, %): 206 (7.7) [M]+, 205 (5.5) [M – H]+,
192 (11.0), 191 (100) [M – CH3]+, 173 (26.7)
[M – SH]+, 165 (13.2) [M – C3H5]+, 158 (9.9), 147
(5.5), 134 (7.1), 125 (6.0), 120 (7.7), 119 (9.3)
[M – SCH2C(CH3)=CH2], 97 (6.0), 93 (28.0), 92 (9.3)
[C5H3N4]+, 71 (6.6), 70 (11.5), 66 (11.0), 65 (11.0), 55
(5.6) [C4H6]+, 53 (12.1), 45 (10.4). Found, %: C 52.45;
H 4.93; N 27.14. C9H10N4S. Calculated, %: C 52.41;
H 4.89; N 27.16. M 206.27.
1
(9). Compounds 8 and 9 showed in the H NMR
spectra a singlet of methyl protons at δ 2.00–2.10 ppm
and a SCH2 signal at δ 4.10–4.20 and 4.35–4.50 ppm,
respectively; the SCH2 signal of 4 and 6 was located at
1
δ 4.70 and 4.65 ppm, respectively. In the H NMR
spectra of 4, 6, 8, and 9 aromatic proton signals
characteristically appeared in a weaker field due to the
presence of positive charge.
(7E)-7-Bromomethylidene-7,8-dihydro-3H-[1,3]-
thiazolo[2,3-i]purin-6-ium bromide (4). Compound
2a, 0.095 g (0.5 mmol), was added to a solution of
0.052 mL (1 mmol) of bromine in 5 mL of acetic acid.
After 24 h, (7E)-7-bromomethylidene-7,8-dihydro-3H-
[1,3]thiazolo[2,3-i]purin-6-ium tribromide (3) was
filtered off and treated with acetone, and the yellow
precipitate was filtered off. Yield 0.109 g (62%),
mp 137–139°C (decomp.). 1H NMR spectrum, δ, ppm:
4.73 d (2H, SCH2), 8.20 t (1H, =CHBr), 9.00 s (1H,
2-H), 9.84 s (1H, 5-H). Found, %: C 27.49; H 1.75;
N 16.00. C8H6Br2N4S. Calculated, %: C 27.45; H 1.73;
N 16.01.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
Bruker DRX-400 and Bruker Avance II spectrometers
at 400 and 126 MHz, respectively, using DMSO-d6 as
solvent and tetramethylsilane as reference. The IR
spectra were measured on a Bruker Tensor 27 spec-
trometer with Fourier transform. The mass spectra
(electron impact, 70 eV) were obtained on a Shimadzu
GCMS-QP2010 Ultra instrument.
(7E)-7-Iodomethylidene-7,8-dihydro-3H-[1,3]-
thiazolo[2,3-i]purin-6-ium iodide (6). Compound 2a,
0.095 g (0.5 mmol), was added to a solution of 0.254 g
(1 mmol) of iodine in 5 mL of acetic acid. After 24 h,
(7E)-7-iodomethylidene-7,8-dihydro-3H-[1,3]thiazolo-
[2,3-i]purin-6-ium triiodide (5) was filtered off and
dissolved in acetone, sodium iodide was added, and the
light yellow precipitate of iodide 6 was filtered off.
Yield 0.133 g (60%), mp 250–254°C (decomp.).
1H NMR spectrum, δ, ppm: 4.64 s (2H, SCH2), 8.12 s
(1H, CHI), 8.97 s (1H, 2-H), 9.73 s (1H, 5-H).
13C NMR spectrum, δC, ppm: 39.73 (SCH2), 75.47
(CHI), 126.67 (C9b), 141.28 (C7), 142.58 (C5), 149.79
(C2), 151.22 (C3a), 159.27 (C9a). Found, %: C 21.61;
H 1.38; N 12.65. C8H6I2N4S. Calculated, %: C 21.64;
H 1.36; N 12.62.
Compounds 2a and 2b (general procedure). Potas-
sium hydroxide, 112 mg (2 mmol), was dissolved in
10 mL of water and 340 mg (2 mmol) of purine-6-thiol
and a solution of 2 mmol of methallyl chloride or
propargyl bromide in 1 mL of ethanol were added. The
mixture was stirred for 2 h, and the precipitate was
filtered off, washed with water, and dried.
6-(Prop-2-yn-1-ylsulfanyl)purine (2a). Yield
330 mg (87%), gray powder, mp 180–182°C
(decomp.) [11]. 1H NMR spectrum, δ, ppm: 3.15 t (1H,
CH, J = 2.5 Hz), 4.23 d (2H, SCH2, J = 2.7 Hz), 8.48 s
(1H, 8-H), 8.74 s (1H, 2-H), 13.59 s (1H, NH). Mass
spectrum, m/z (Irel, %): 190 (17.0) [M]+, 119 (5.0)
[M – SCH2C≡CH]+, 97 (5.0), 93 (11.3), 92 (5.6)
[C5H3N4]+, 72 (9.9), 71 (12.7), 70 (24.0), 69 (14.1), 66
(17.0), 65 (14.0), 53 (14.0), 45 (31.0), 44 (5.6), 40
(8.5), 39 (100) [C3H3]+, 38 (52.1), 37 (18.3).
7-(Iodomethyl)-7-methyl-7,8-dihydro-1H-[1,3]-
thiazolo[2,3-i]purin-6-ium iodide (8). Compound 2b,
0.103 g (0.5 mmol), was added to a solution of 0.254 g
(1 mmol) of iodine in 5 mL of acetic acid. After 24 h,
the solvent was evaporated, the residue was dissolved
in acetone, sodium iodide was added, and the precip-
itate was filtered off. Yield 0.111 g (48%), mp 139–
6-(2-Methylprop-2-en-1-ylsulfanyl)purine (2b).
Yield 351 mg (84%), gray powder, mp 159–160°C. IR
spectrum, ν, cm–1: 3328, 3175, 3058, 2977, 2941,
2788, 2661, 2554, 1870, 1692, 1654, 1631, 1590,
1570, 1466, 1430, 1420, 1385 (=CH), 1326, 1263,
1242, 1230, 1158, 1128, 1054, 1014, 998, 950 (=CH),
927, 902, 882, 848, 795, 767, 716, 678, 645, 630, 599,
1
140°C. H NMR spectrum, δ, ppm: 2.04 s (3H, CH3),
3.99 s (2H, SCH2), 4.14 d (2H, CH2Br, J = 11.3 Hz),
8.78 s (1H, 2-H), 9.32 s (1H, 5-H). 13C NMR spec-
trum, δC, ppm: 13.96 (CH3), 25.62 (CH2I), 31.29
1
541, 518, 503, 422. H NMR spectrum, δ, ppm: 1.82 s
(3H, CH3), 4.10 s (2H, SCH2), 4.89 s and 5.08 s (2H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018

OSHEKO et al.
1410
(SCH2), 43.10 (C7), 128.17 (C9b), 143.71 (C5), 155.26
(C2), 155.90 (C3a), 172.47 (C9a). Found, %: C 23.47;
H 2.17; N 12.21. C9H10I2N4S. Calculated, %: C 23.50;
H 2.19; N 12.18.
2. Zercher, C.K. and Fedor, L.R., Carbohydr. Res., 1987,
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3. Volonté, C. and Greene, L.A., J. Neurochem., 1992,
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p. 579.
7-(Bromomethyl)-7-methyl-7,8-dihydro-1H-[1,3]-
thiazolo[2,3-i]purin-6-ium bromide (9). Compound
2b, 0.103 g (0.5 mmol), was added to a solution of
0.026 mL (0.5 mmol) of bromine in 5 mL of acetic
acid. After 24 h, the white crystals were filtered off.
Yield 0.119 g (65%), mp 230–233°C (decomp.).
1H NMR spectrum, δ, ppm: 2.06 s (3H, CH3), 4.05 d
and 4.14 d (1H each, SCH2, J = 12.3 Hz), 4.37 d and
4.48 d (1H each, CH2Br, J = 11.4 Hz), 9.02 s (1H, 2-H),
9.59 s (1H, 5-H). Found, %: C 23.51; H 2.21; N 12.16.
C9H10I2N4S. Calculated, %: C 23.50; H 2.19; N 12.18.
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This study was performed under financial support
by the Government of the Russian Federation
(resolution no. 211, March 16, 2013; contract
no. 02.A03.21.0011) in the framework of state assign-
ment no 4.9665.2017/8.9.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 9 2018