Synthesis of 7-iodo(arylsulfanyl)methyl-7,8-dihydro-[1,3]thiazolo[2,3-i] purinium pentaiodide (perchlorates) and their transformation into 4-amino-5-(1,3-thiazol-2-yl)imidazole derivatives

Article abstract of DOI:10.1134/S1070428013010211

Intramolecular electrophilic cyclization of 6-allylsulfanylpurine by the action of iodine and arenesulfenyl chlorides gave 7-iodomethyl-7,8-dihydro[1,3] thiazolo[2,3-i]purin-6-ium pentaiodide and 7-arylsulfanylmethyl-7,8-dihydro[1,3] thiazolo[2,3-i]purin-

Full text of DOI:10.1134/S1070428013010211

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 1, pp. 123–129. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © R.I. Vas’kevich, A.I. Vas’kevich, E.B. Rusanov, V.I. Staninets, M.V. Vovk, 2013, published in Zhurnal Organicheskoi Khimii, 2013,
Vol. 49, No. 1, pp. 128–134.
Synthesis of 7-Iodo(arylsulfanyl)methyl-7,8-dihydro-
[1,3]thiazolo[2,3-i]purinium Pentaiodide (Perchlorates) and Their
Transformation into 4-Amino-5-(1,3-thiazol-2-yl)imidazole
Derivatives
R. I. Vas’kevich, A. I. Vas’kevich, E. B. Rusanov, V. I. Staninets, and M. V. Vovk
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, ul. Murmanskaya 5, Kiev, 02660 Ukraine
e-mail: vaskevich@ioch.kiev.ua
Received May 30, 2012
Abstract—Intramolecular electrophilic cyclization of 6-allylsulfanylpurine by the action of iodine and arene-
sulfenyl chlorides gave 7-iodomethyl-7,8-dihydro[1,3]thiazolo[2,3-i]purin-6-ium pentaiodide and 7-arylsul-
fanylmethyl-7,8-dihydro[1,3]thiazolo[2,3-i]purin-6-ium perchlorates, respectively. 7-Iodomethyl-7,8-dihydro-
[1,3]thiazolo[2,3-i]purin-6-ium iodide reacted with sodium and potassium alkoxides to produce alkyl
N-[5-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-4-yl]formimidates, and its reaction with secondary cyclic amines
afforded 5-(4-methyl-1,3-thiazol-2-yl)-N-[morpholin-4-yl(or piperidin-1-yl)methylidene]-1H-imidazol-4-
amines. Successive treatment of 7-arylsulfanylmethyl-7,8-dihydro[1,3]thiazolo[2,3-i]purin-6-ium perchlorates
with sodium acetate and morpholine led to the formation of 5-(4-arylsulfanylmethyl-4,5-dihydro-1,3-thiazol-2-
yl)-N-(morpholin-4-ylmethylidene)-1H-imidazol-4-amines.
DOI: 10.1134/S1070428013010211
Intramolecular electrophilic cyclization of 2-allyl-
sulfanylpirimidines [1, 2] and their fused analogs [3–5]
provides a convenient method for the synthesis of
[1,3]thiazolo[3,2-a]pyrimidine derivatives. On the
other hand, analogous transformations of compounds
containing an allylsulfanyl group in position 4 of the
pyrimidine ring, e.g., 4-allylsulfanylquinazolines [6, 7]
or 6-allylsulfanylpurines [8] were not reported. Taking
into account pronounced therapeutic effect of 6-sul-
fanylpurine [9] and its S-alkyl derivatives [10–13],
their chemical modification seems to be important
from the viewpoints of both synthetic and biological
applications.
tem by condensation of 6-sulfanylpurine with 1,2-di-
haloethanes [12, 13], these compounds permanently
attract researchers’ attention [14, 15]. Other versions of
their synthesis have not found practical application.
Therefore, we believed it reasonable to use for this
purpose intramolecular electrophilic cyclization of
6-allylsulfanylpurine (І) by the action of iodine and
arenesulfenyl chlorides.
Compound І reacted with 3 equiv of iodine in
chloroform at room temperature to give 7-iodomethyl-
7,8-dihydro[1,3]thiazolo[2,3-i]purin-6-ium pentaiodide
(ІІ) in quantitative yield as a result of selective intra-
molecular cyclization. The subsequent treatment of II
with sodium iodide in acetone quantitatively afforded
the corresponding iodide ІІІ (Scheme 1). The structure
Since the first synthesis of representatives of the
7,8-dihydro[1,3]thiazolo[2,3-i]purine heterocyclic sys-
Scheme 1.
H2C
S
N
S
S
I
I
H
N
H
N
H
N
3I2
NaI
N
N
N
I5
I
N
N
N
N
N
I
II
III
123

VAS’KEVICH et al.
124
Scheme 2.
HN
N
S
RONa
N
N
Me
O
R
Va, Vb
S
S
H
OEt
H2C
H2C
EtOH, KOH
AcONa
N
N
N
N
N
N
III
Vb
EtO–
N
N
K+
IV
A
HN
N
N
NH
X
S
N
N
X
Me
VIa, VIb
V, R = Me (a), Et (b); VI, X = CH2 (a), O (b).
of ІІ and ІІІ is consistent with the IR and NMR data.
The IR spectra of II and III contained an absorption
band in the region 1630–1610 cm–1 due to stretching
vibrations of the iminium fragment, and their 1H NMR
spectra displayed multiplet signals from protons in the
dihydrothiazole ring (δ 3.83–5.84 ppm) and singlets
from 2-H and 5-H at δ 8.97 and 9.47–9.48 ppm,
respectively.
zolopurine system, which could ensure a novel syn-
thetic approach to 4-amino derivatives of bihetero-
cyclic thiazolylimidazole ensemble. Monthomery et al.
[13] previously described cleavage of the thiazole ring
in 7,8-dihydro-3H-thiazolo[2,3-i]purinium bromides in
reactions with benzenethiols.
We found that this reaction is more general. Thia-
zolopurinium iodide ІІІ reacted with excess cyclic
secondary amines (piperidine and morpholine) at room
temperature to produce 4-amino-5-thiazolylimidazole
derivatives VІa and VIb in high yield. Compounds Va,
Molecule IІІ possesses two electrophilic centers
and is a convenient model for studying reactions with
nucleophiles. By treatment of III with sodium acetate
in ethanol at room temperature we obtained 7-methyli-
dene-7,8-dihydro[1,3]thiazolo[2,3-i]purine (IV)
(Scheme 2). The reactions of III with sodium methox-
ide or ethoxide followed a much more complex pattern
and unexpectedly resulted in the formation of alkyl
N-[5-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-4-yl]-
formimidates Va and Vb. Most probably, compound
IV was initially formed as intermediate. This assump-
tion was confirmed by the isolation of Vb when
7-methylidene derivative IV was heated to 60°C in
ethanol in the presence of potassium hydroxide. The
process is most likely to involve opening of the py-
rimidine ring in intermediate A by the action of alkox-
ide ion and simultaneous or subsequent 1,3-prototropic
shift in the dihydrothiazole fragment.
1
Vb, VІa, and VIb showed in the H NMR spectra
singlets from protons in the thiazole and imidazole
rings at δ 6.98–7.18 and 8.40–8.62 ppm, respectively,
and a singlet at δ 7.43–7.58 ppm from the formamidine
CH proton. The exocyclic amidine fragment gave
a singlet at δC 151–156 ppm in the 13C NMR spectra.
The structure of compound VIa was unambigu-
ously proved by X-ray analysis (Figs. 1, 2). The thia-
zole and imidazole rings in molecule VIa are charac-
terized by standard geometric parameters. Both hetero-
rings are planar within 0.005 and 0.0027 Å, respec-
tively, and the dihedral angle between their planes is
11.1(2)°. The N4=C8 double bond length [1.288(3) Å]
does not differ from the corresponding standard value,
whereas the formally single N4–C7 [1.383(3) Å] and
N5–C8 bonds [1.341(3) Å] are appreciably shortened so
that they approach those typical of conjugated or
The described reaction may be regarded as a new
version of fragmentation of pyrimidine ring in the thia-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 1 2013

SYNTHESIS OF 7-IODO(ARYLSULFANYL)METHYL-7,8-DIHYDRO[1,3]THIAZOLO...
125
Scheme 3.
HN
N
NH
S
S
ArS
ArS
ArSCl (VIIa–VIIc)
LiClO4
S
N
H
N
O
AcONa
N
N
N
N
N
N
I
ClO4
N
O
N
N
ArS
VIIIa–VIIIc
IXa–IXc
Xa–Xc
Ar = Ph (a), 4-MeC6H4 (b), 4-O2NC6H4 (c).
heteroaromatic systems. The sum of the bond angles at
the N5 atom is 358.2(2)°, indicating electron density
delocalization over the molecule. Molecules VIa in
crystal (Fig. 2) form infinite chains due to hydrogen
bonding N2–H2N ···N3A along the a crystallographic
axis [N2–H2N 0.93(3), N2 · · · N3A 2.840(3) Å,
∠N2H2NN3A 170(2)°; here, the superscript “A” refers to
a nitrogen atom related to the base atoms through the
symmetry operation x – 5, 1.5 – y, –z.
crystal on a Bruker Smart Apex II diffractometer
(λMoKα irradiation, graphite monochromator, θmax
28.36°, spherical segment –9 ≤ h ≤ 12, –14 ≤ k ≤ 14,
–18 ≤ l ≤ 19). C13H17N5S, M 275.38; rhombic crystals,
space group P212121; unit cell parameters: a =
9.2666(5), b = 10.8871(5), c = 14.3498(6) Å; V =
=
C6
N3
C7
N2
C8
6-Allylsulfanylpurine І was also subjected to intra-
molecular cyclization by the action of arenesulfenyl
chlorides VIIa–VIIc in acetic acid in the presence of
an equimolar amount of lithium perchlorate [16, 17]
(Scheme 3). As a result, we isolated 85–89% of
7-arylsulfanylmethyl-7,8-dihydro[1,3]thiazolo[2,3-i]-
purin-6-ium perchlorates VIIІa–VIIIc. Treatment of
the latter with sodium acetate in ethanol smoothly af-
forded free bases IXa–IXc which reacted with excess
morpholine under mild conditions to give new imida-
zoles Xa–Xc containing a formamidine fragment in
position 4 and a 4-(arylsulfanylmethyl)dihydrothia-
zolyl substituent in position 5. The structure of Xa–Xc
was confirmed by their 1H and 13C NMR spectra which
contained signals at δ 7.46–7.48 ppm and δC 152 ppm
from the formamidine CH fragment.
N5
C13
C5
N1
C1
N4
C9
C10
C2
C4
S1
C3
C11
C12
Fig. 1. Structure of the molecule of 5-(4-methyl-1,3-thiazol-
2-yl)-N-[(piperidin-1-yl)methylidene]-1H-imidazol-4-amine
(VIa) according to the X-ray diffraction data. Principal bond
lengths (Å) and bond angles (deg): S1–C1 1.729(2), N1–C1
1.316(3), N1–C2 1.378(3), C2–C3 1.345(4), S1–C3 1.711(3),
C1–C5 1.432(3), N2–C5 1.388(3), N2–C6 1.333(3), N3–C6
1.323(3), N3–C7 1.376(3), C5–C7 1.381(3); N1C1S1
114.15(18), C1N1C2 110.8(2), C3C2N1 114.9(2), C2C3S1
111.1(2), C3S1C1 89.01(13), C6N2C5 106.8(2), N3C6N2
113.1(2), C6N3C7 104.8(2), N3C7C5 109.9(2), C7C5N2
105.3(2), C8N4C7 117.0(2), N4C8N5 123.5(3).
EXPERIMENTAL
The IR spectra were recorded in KBr on a UR-20
spectrometer. The 1H and 13C NMR spectra were meas-
ured on a Bruker Avance DRX-500 spectrometer at
400 and 125.75 MHz, respectively, using tetramethyl-
silane as internal reference. The mass spectra of VIa,
VIb, IXa–IXc, and Xb were obtained on an Agilent
1100/DAD/HSD/VLG 119562 instrument.
N3aa
N3a
N2aa
N3c
N2c
N3b
N2a
N2
N2b
N3
6-Allylsulfanyl-7H-purine (I) was synthesized
according to the procedure described in [8].
The X-ray diffraction data for compound VІa were
acquired at 173 K from a 0.14×0.18×0.35-mm single
Fig. 2. Hydrogen bond chains in the crystalline structure of
compound VIa along the a crystallographic axis.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 1 2013

VAS’KEVICH et al.
126
1447.70(12) Å3; Z = 4; dcalc = 1.263 g/cm3; μ =
0.218 mm–1; F(000) = 584. Total of 17399 reflection
intensities were measured, 3591 of which were inde-
pendent (averaging R-factor 0.0734). A correction for
absorption was introduced by the multiscan method
using SADABS program (Tmin/Tmax = 0.72674). The
structure was solved by the direct method and was
refined by the least-squares procedure using Bruker
SHELXTL software package [18]. All non-hydrogen
atoms were refined in anisotropic approximation.
Hydrogen atoms were visualized objectively, and their
positions were refined in isotropic approximation. The
refinement was performed from 2161 reflections with
I > 2σ(I) {240 variables, 9.0 reflections per variable;
weight scheme ω = 1/[σ2(Fo2) + (0.0373R)2], where
R = (Fo2 + 2Fc2)/3}. The final divergence factors were
R1(F) = 0.0501, wR2(F2) = 0.0805 for reflections with
I > 2σ(I) and R1(F) = 0.1082, wR2(F2) = 0.0968 for all
reflections; goodness of fit 0.993; Flack parameter
–0.04(9). The residual electron density from the
Fourier difference series after last iteration was 0.19
and –0.27 e/Å3. The set of crystallographic data for
compound VIa was deposited to the Cambridge Crys-
tallographic Data Centre (entry no. CCDC 880940).
C 21.51; H 1.77; I 56.86; N 12.47; S 7.13. C8H8I2N4S.
Calculated, %: C 21.54; H 1.81; I 56.90; N 12.56;
S 7.19.
7-Methylidene-7,8-dihydro[1,3]thiazolo[2,3-i]-
purine (IV). A mixture of 0.45 g (1 mmol) of com-
pound III and 0.16 g (2 mmol) of sodium acetate in
50 ml of ethanol was stirred for 48 h at room tempera-
ture. The precipitate was filtered off, washed with
water and ethanol, and dried in air. Yield 0.12 g (63%),
mp >320°C. IR spectrum, ν, cm–1: 1640, 1600, 1500,
1
1420, 1400, 1360, 1290, 1240, 1150, 1020. H NMR
spectrum, δ, ppm: 4.56 m (2H, CH2), 5.48 m and
6.12 m (1H each, =CH2), 8.38 s (1H, 2-H), 9.41 s
(1H, 5-H). Found, %: C 50.44; H 3.11; N 29.37;
S 16.74. C8H6N4S. Calculated, %: C 50.51; H 3.18;
N 29.45; S 16.86.
Alkyl N-[5-(4-methyl-1,3-thiazol-2-yl)-1H-imid-
azol-4-yl]formimidates Va and Vb (general proce-
dures). a. Compound III, 0.45 g (1 mmol), was added
to a solution of sodium alkoxide prepared from 0.07 g
(3 mmol) of metallic sodium and 30 ml of methanol or
ethanol. The mixture was stirred for 6 h and evaporat-
ed under reduced pressure, and the residue was treated
with diethyl ether. The ether extract was washed with
water, dried over MgSO4, and evaporated under
reduced pressure, and the solid residue was filtered off
and washed with hexane.
7-Iodomethyl-7,8-dihydro[1,3]thiazolo[2,3-i]-
purin-6-ium pentaiodide (II). A solution of 3.81 g
(15 mmol) of iodine in 300 ml of chloroform was
added at room temperature to a suspension of 0.96 g
(5 mmol) of compound І in 20 ml of chloroform, and
the mixture was stirred for 48 h. The black crystalline
solid was filtered off, washed with 30 ml of hexane,
and dried in air. Yield 4.72 g (99%), mp 158–160°C.
IR spectrum, ν, cm–1: 1610, 1580, 1490, 1420, 1260,
b. A mixture of 0.06 g (1 mmol) of potassium hy-
droxide and 0.19 g (1 mmol) of compound IV in 30 ml
of ethanol was heated for 10 min at 60°C. The solvent
was removed under reduced pressure, and the precip-
itate was filtered off, washed with water, and dried.
1
Methyl N-[5-(4-methyl-1,3-thiazol-2-yl)-1H-
imidazol-4-yl]formimidate (Va). Yield 0.14 g (63%)
(a), mp 132–134°C. IR spectrum, ν, cm–1: 1640, 1590,
1530, 1420, 1350, 1290, 1230, 1180, 1110, 1020, 970,
920. H NMR spectrum, δ, ppm: 3.83–3.87 m (1H,
CH), 3.92–3.93 m (2H, CH2), 4.24–4.31 m (1H, CH),
5.71–5.84 m (1H, CH), 8.97 s (1H, 2-H), 9.47 s (1H,
5-H). Found, %: C 10.02; H 0.83; I 79.56; N 5.81;
S 3.31. C8H8I6N4S. Calculated, %: C 10.08; H 0.85;
I 79.84; N 5.87; S 3.36.
1
930. H NMR spectrum, δ, ppm: 2.40 s (3H, CH3),
3.91 s (3H, OCH3), 7.18 s (1H, 5′-H), 7.58 s (1H,
N=CH), 8.62 s (1H, 2-H), 12.88 s (1H, NH). 13C NMR
spectrum, δC, ppm: 16.71 (CH3), 53.76 (OCH3), 113.42
(C5′), 116.66 (C4), 134.85 (C2), 143.81 (C5), 151.13
(C4′), 155.76 (C2′), 156.70 (N=CH). Found, %:
C 48.55; H 4.44; N 25.19; S 14.35. C9H10N4OS. Cal-
culated, %: C 48.63; H 4.53; N 25.21; S 14.43.
7-Iodomethyl-7,8-dihydro[1,3]thiazolo[2,3-i]-
purin-6-ium iodide (III). A solution of 0.90 g
(6 mmol) of sodium iodide in 20 ml of acetone was
added under stirring to a solution of 1.91 g (2 mmol) of
compound II in 30 ml of acetone. After a time, the
yellow crystalline solid was filtered off, washed with
acetone, and dried in air. Yield 0.87 g (98%), mp 223–
225°C. IR spectrum, ν, cm–1: 3030, 1630, 1540, 1500,
Ethyl N-[5-(4-methyl-1,3-thiazol-2-yl)-1H-imid-
azol-4-yl]formimidate (Vb). Yield 0.16 g (66%) (a),
0.16 g (67%) (b); mp 138–139°C. IR spectrum, ν,
cm–1: 3130, 3020, 2880, 1630, 1590, 1520, 1440, 1350,
1
1400, 1360, 1250, 1220, 1190, 1120, 1040. H NMR
spectrum, δ, ppm: 3.84–3.88 m (1H, CH), 3.93–3.95 m
(2H, CH2), 4.26–4.32 m (1H, CH), 5.78–5.82 m (1H,
CH), 8.97 s (1H, 2-H), 9.48 s (1H, 5-H). Found, %:
1
1290, 1220, 1110, 1020. H NMR spectrum, δ, ppm:
1.37 t (3H, CH3, J = 6.8 Hz), 2.39 s (3H, CH3), 4.38 q
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SYNTHESIS OF 7-IODO(ARYLSULFANYL)METHYL-7,8-DIHYDRO[1,3]THIAZOLO...
127
(2H, CH2, J = 6.8 Hz), 7.12 s (1H, 5′-H), 7.57 s (1H,
N=CH), 8.58 s (1H, 2-H), 12.85 s (1H, NH). 13C NMR
spectrum, δC, ppm: 14.00 (CH3CH2), 16.69 (4′-CH3),
62.36 (OCH2), 113.40 (C5′), 116.23 (C4), 134.93 (C2),
143.72 (C5), 151.10 (C4′), 155.71 (C2′), 156.12
(N=CH). Found, %: C 50.76; H 5.04; N 23.61;
S 13.42. C10H12N4OS. Calculated, %: C 50.83; H 5.12;
N 23.71; S 13.57.
fenyl chloride VIIa–VIIc in 10 ml of acetic acid was
added at 15–20°C to a suspension of 0.38 g (2 mmol)
of compound I and 0.22 g (2 mmol) of LiClO4 in
20 ml of acetic acid. The mixture was stirred for 5–6 h,
left to stand for 12 h, and evaporated, and the precip-
itate was filtered off, washed with diethyl ether on
a filter, and dried in air.
7-[(Phenylsulfanyl)methyl]-7,8-dihydro[1,3]-
thiazolo[2,3-i]purin-6-ium perchlorate (VIIІa).
Yield 0.68 g (85%), mp 107–109°C. IR spectrum, ν,
cm–1: 1620, 1570, 1500, 1410, 1350, 1260, 1120, 1090,
5-(4-Methyl-1,3-thiazol-2-yl)-N-(dialkylamino-
methylidene)-1H-imidazol-4-amines VIa and VIb
(general procedure). A mixture of 0.45 g (1 mmol) of
compound III and 15 ml of piperidine or morpholine
was stirred for 20 h at room temperature. Excess amine
was distilled off, and the solid residue was filtered
off, washed with water, dried, and recrystallized from
ethanol.
1
920, 880. H NMR spectrum, δ, ppm: 3.71–3.88 m
(2H, CH2), 3.97–4.00 m (1H, CH), 4.23–4.28 m (1H,
CH), 5.77–5.83 m (1H, CH), 7.09 t (1H, Harom, J =
7.6 Hz), 7.17 t (2H, Harom, J = 7.6 Hz), 7.35 d (2H,
Harom, J = 8.0 Hz), 8.89 s (1H, 2-H), 9.31 s (1H, 5-H).
13C NMR spectrum, δC, ppm: 36.11 (C8), 36.14
(CH2S), 67.82 (C7), 126.54 (Carom), 128.88 (2C, Carom),
128.92 (2C, Carom), 133.17 (Carom), 145.70 (C2), 149.32
(C5), 151.73 (C9b), 158.55 (C3a), 194.06 (C9a). Found,
%: C 41.88; H 3.22; Cl 8.79; N 13.94; S 15.91.
C14H13ClN4O4S2. Calculated, %: C 41.95; H 3.27;
Cl 8.84; N 13.98; S 16.00.
5-(4-Methyl-1,3-thiazol-2-yl)-N-(piperidin-1-yl-
methylidene)-1H-imidazol-4-amine (VIa). Yield
0.17 g (63%), mp 194–195°C. IR spectrum, ν, cm–1:
2940, 2860, 1620, 1580, 1520, 1420, 1360, 1340,
1
1290, 1250, 1210, 1100, 1020, 1000. H NMR spec-
trum, δ, ppm: 1.56 m (4H, CH2), 1.64 m (2H, CH2),
2.36 s (3H, CH3), 3.40 m (2H, CH2), 3.69 m (2H,
CH2), 6.96 s (1H, 5′-H), 7.43 s (1H, N=CH), 8.40 s
(1H, 2-H), 12.41 s (1H, NH). 13C NMR spectrum, δC,
ppm: 16.78 (CH3), 24.16 (CH2), 24.54 (CH2), 26.29
(CH2), 42.61 (CH2), 49.59 (CH2), 111.62 (C5′), 113.66
(C4), 134.10 (C2), 148.15 (C5), 150.45 (C4′), 152.03
(N=CH), 156.93 (C2′). Mass spectrum: m/z 276
[M + 1]+. Found, %: C 56.56; H 6.16; N 25.38;
S 11.58. C13H17N5S. Calculated, %: C 56.70; H 6.22;
N 25.43; S 11.64. M 275.37.
7-[(4-Methylphenylsulfanyl)methyl]-7,8-dihydro-
[1,3]thiazolo[2,3-i]purin-6-ium perchlorate (VIIІb).
Yield 0.74 g (89%), mp 104–106°C. IR spectrum, ν,
cm–1: 3050, 2970, 1620, 1580, 1500, 1410, 1360, 1260,
1
1120, 920, 890. H NMR spectrum, δ, ppm: 2.16 s
(3H, CH3), 3.62–3.89 m (2H, CH2), 3.95–4.00 m (1H,
CH), 4.21–4.28 m (1H, CH), 5.76–5.84 m (1H, CH),
6.93 d (2H, Harom, J = 7.5 Hz), 7.21 d (2H, Harom, J =
8.4 Hz), 8.91 s (1H, 2-H), 9.28 s (1H, 5-H). Found, %:
C 43.36; H 3.62; Cl 8.49; N 13.41; S 15.32.
C15H15ClN4O4S2. Calculated, %: C 43.42; H 3.64;
Cl 8.55; N 13.50; S 15.46.
5-(4-Methyl-1,3-thiazol-2-yl)-N-(morpholin-4-yl-
methylidene)-1H-imidazol-4-amine (VIb). Yield
0.23 g (84%), mp 111–113°C. IR spectrum, ν, cm–1:
3020, 1620, 1580, 1520, 1440, 1350, 1300, 1240,
7-[(4-Nitrophenylsulfanyl)methyl]-7,8-dihydro-
[1,3]thiazolo[2,3-i]purin-6-ium perchlorate (VIIІc).
Yield 0.76 g (87%), mp 205–207°C. IR spectrum, ν,
cm–1: 3130, 1630, 1580, 1500, 1410, 1340, 1260, 1110,
1
1190, 1180, 1120, 1030, 920. H NMR spectrum, δ,
ppm: 2.36 s (3H, CH3), 3.48 m (2H, CH2), 3.67 m (6H,
CH2), 7.02 s (1H, 5′-H), 7.47 s (1H, N=CH), 8.44 s
(1H, 2-H), 12.51 s (1H, NH). 13C NMR spectrum, δC,
ppm: 16.77 (CH3), 42.80 (CH2), 48.44 (CH2), 65.45
(CH2), 66.57 (CH2), 111.91 (C5′), 113.60 (C4), 134.43
(C2), 148.27 (C5), 150.53 (C4′), 151.86 (N=CH),
156.38 (C2′). Mass spectrum: m/z 278 [M + 1]+. Found,
%: C 51.88; H 5.33; N 25.16; S 11.42. C12H15N5OS.
Calculated, %: C 51.97; H 5.45; N 25.25; S 11.56.
M 277.35.
1
1090, 1060. H NMR spectrum, δ, ppm: 3.85–4.02 m
(3H, CH, CH2), 4.25–4.30 m (1H, CH), 5.84–5.89 m
(1H, CH), 7.62 d (2H, Harom, J = 8.4 Hz), 8.03 d (2H,
Harom, J = 9.2 Hz), 8.92 s (1H, 2-H), 9.39 s (1H, 5-H).
13C NMR spectrum, δC, ppm: 34.52 (C8), 36.56
(7-CH2), 67.33 (C7), 123.71 (2C, Carom), 127.85 (2C,
Carom), 143.99 (Carom), 145,14 (Carom), 145.91 (C2),
149.50 (C5), 151.91 (C9b), 158.58 (C3a), 194.10 (C9a).
Found, %: C 37.56; H 2.67; Cl 7.86; N 15.63; S 14.31.
C14H12ClN5O6S2. Calculated, %: C 37.71; H 2.71;
Cl 7.95; N 15.71; S 14.38.
7-Arylsulfanylmethyl-7,8-dihydro[1,3]thiazolo-
[2,3-i]purin-6-ium perchlorates VIIІa–VIIIc (gen-
eral procedure). A solution of 2.1 mmol of arenesul-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 1 2013

VAS’KEVICH et al.
128
7-Arylsulfanylmethyl-7,8-dihydro[1,3]thiazolo-
m/z 346 [M + 1]+. Found, %: C 48.57; H 3.18;
N 20.14; S 18.53. C14H11N5O2S2. Calculated, %:
C 48.68; H 3.21; N 20.28; S 18.57. M 345.40.
[2,3-i]purines IXa–IXc (general procedure). A mix-
ture of 1 mmol of compound VIIІa–VIIIc and 0.16 g
(2 mmol) of sodium acetate in 50 ml of ethanol was
stirred for 4 h at room temperature. The solvent was
removed under reduced pressure, and the precipitate
was filtered off, washed with water, and dried.
5-(4-Arylsulfanylmethyl-4,5-dihydro-1,3-thiazol-
2-yl)-N-(morpholin-4-ylmethylidene)-1H-imidazol-
4-amines Xa–Xc were synthesized as described above
for compound VIb from 1 mmol of IXa–IXc and
15 ml of morpholine.
7-[(Phenylsulfanyl)methyl]-7,8-dihydro[1,3]thia-
zolo[2,3-i]purine (IXa). Yield 0.27 g (91%), mp 153–
155°C. IR spectrum, ν, cm–1: 1610, 1500, 1450, 1400,
N-(Morpholin-4-ylmethylidene)-5-(4-phenylsul-
fanylmethyl-4,5-dihydro-1,3-thiazol-2-yl)-1H-imid-
azol-4-amine (Xa). Yield 0.29 g (75%), mp 159–
161°C. IR spectrum, ν, cm–1: 3220, 1620, 1580, 1440,
1370, 1290, 1230, 1180, 1120, 1070, 1020, 980, 930.
1H NMR spectrum, δ, ppm: 3.07–3.18 m (2H, CH2),
3.33–3.51 m (4H, CH2), 3.64 m (6H, CH2), 4.54–
4.69 m (1H, CH), 7.22 t (1H, Harom, J = 7.2 Hz), 7.35 t
(2H, Harom, J = 7.2 Hz), 7.42 d (2H, Harom, J = 7.8 Hz),
7.48 s (1H, N=CH), 8.35 s (1H, 2-H), 12.34 s (1H,
NH.). 13C NMR spectrum, δC, ppm: 36.17 (C5′), 37.53
(4′-CH2), 43.31 (NCH2), 49.02 (NCH2), 66.02 (OCH2),
67.14 (OCH2), 74.00 (C4′), 113.03 (C4), 126.31 (Carom),
128.83 (2C, Carom), 129.59 (2C, Carom), 136.43 (Carom),
136.68 (C2), 151.59 (C5), 152.48 (N=CH), 156.81
(C2′). Found, %: C 55.67; H 5.42; N 18.03; S 16.42.
C18H21N5OS2. Calculated, %: C 55.79; H 5.46;
N 18.07; S 16.55.
1
1360, 1250, 1120, 1100, 890. H NMR spectrum, δ,
ppm: 3.68–3.81 m (2H, CH2), 3.87–3.90 m (1H, CH),
4.15–4.20 m (1H, CH), 5.65–5.70 m (1H, CH), 7.13 t
(1H, Harom, J = 7.6 Hz), 7.22 t (2H, Harom, J = 7.6 Hz),
7.37 d (2H, Harom, J = 7.6 Hz), 8.61 s (1H, 2-H), 9.10 s
(1H, 5-H). 13C NMR spectrum, δC, ppm: 35.48 (C8),
35.83 (7-CH2), 66.87 (C7), 126.46 (Carom), 128.74 (2C,
C
arom), 128.94 (3C, Carom, C9b), 133.42 (Carom), 143.11
(C2), 153.71 (C9a), 156.09 (C5), 156.56 (C3a). Mass
spectrum: m/z 301 [M + 1]+. Found, %: C 55.88;
H 3.96; N 18.53; S 21.27. C14H12N4S2. Calculated, %:
C 55.97; H 4.03; N 18.65; S 21.35. M 300.40.
7-[(4-Methylphenylsulfanyl)methyl]-7,8-dihydro-
[1,3]thiazolo[2,3-i]purine (IXb). Yield 0.27 g (86%),
mp 119–121°C. IR spectrum, ν, cm–1: 1610, 1500,
1440, 1410, 1350, 1260, 1170, 1120, 1100, 1080, 920,
1
890. H NMR spectrum, δ, ppm: 2.19 s (3H, CH3),
5-[4-(4-Methylphenylsulfanylmethyl)-4,5-dihy-
dro-1,3-thiazol-2-yl]-N-(morpholin-4-ylmethyli-
dene)-1H-imidazol-4-amine (Xb). Yield 0.29 g
(73%), mp 168–169°C. IR spectrum, ν, cm–1: 3260,
2970, 2930, 1620, 1590, 1430, 1370, 1290, 1240,
3.61–3.78 m (2H, CH2), 3.85–3.89 m (1H, CH), 4.13–
4.18 m (1H, CH), 5.61–5.74 m (1H, CH), 7.00 d (2H,
Harom, J = 7.6 Hz), 7.25 d (2H, Harom, J = 8.0 Hz),
8.60 s (1H, 2-H), 9.06 s (1H, 5-H). 13C NMR spec-
trum, δC, ppm: 20.43 (CH3), 35.47 (C8), 36.57 (7-CH2),
67.08 (C7), 128.18 (C9b), 129.40 (2C, Carom), 129.60
(2C, Carom), 129.61 (Carom), 136.33 (Carom), 143.26 (C2),
154.00 (C9a), 155.74 (C5), 156.44 (C3a). Mass spec-
trum: m/z 315 [M + 1]+. Found, %: C 57.23; H 4.46;
N 17.75; S 20.29. C15H14N4S2. Calculated, %: C 57.30;
H 4.49; N 17.82; S 20.40. M 314.43.
1
1190, 1110, 1070, 1020, 980, 930. H NMR spectrum,
δ, ppm: 2.28 s (3H, CH3), 2.99–3.12 m (2H, CH2),
3.25–3.44 m (4H, CH2), 3.63 m (6H, CH2), 4.52–
4.59 m (1H, CH), 7.16 d (2H, Harom, J = 9.2 Hz),
7.31 d (2H, Harom, J = 7.6 Hz), 7.46 s (1H, N=CH),
8.35 s (1H, 2-H), 12.32 s (1H, NH). 13C NMR spec-
trum, δC, ppm: 21.03 (CH3), 36.04 (C5′), 38.21
(4′-CH2), 43.25 (NCH2), 49.04 (NCH2), 66.02 (OCH2),
67.11 (OCH2), 74.08 (C4′), 113.06 (C4), 129.61 (2C,
Carom), 130.24 (2C, Carom), 132.84 (Carom), 136.03
(Carom), 136.35 (C2), 151.62 (C5), 152.42 (N=CH),
156.63 (C2′). Mass spectrum: m/z 402 [M + 1]+. Found,
%: C 56.71; H 5.67; N 17.38; S 15.84. C19H23N5OS2.
Calculated, %: C 56.83; H 5.77; N 17.44; S 15.97.
M 401.55.
7-[(4-Nitrophenylsulfanyl)methyl]-7,8-dihydro-
[1,3]thiazolo[2,3-i]purine (IXc). Yield 0.34 g (97%),
mp 241–243°C. IR spectrum, ν, cm–1: 1630, 1500,
1
1450, 1400, 1330, 1260, 1180, 1090, 990. H NMR
spectrum, δ, ppm: 3.85–3.93 m (3H, CH, CH2), 4.17–
4.22 m (1H, CH), 5.73–5.77 m (1H, CH), 7.60 d (2H,
Harom, J = 8.4 Hz), 8.03 d (2H, Harom, J = 8.4 Hz),
8.56 s (1H, 2-H), 9.12 s (1H, 5-H). 13C NMR spec-
trum, δC, ppm: 34.49 (C8), 35.75 (7-CH2), 66.42 (C7),
123.64 (2C, Carom), 127.56 (2C, Carom), 128.49 (C9b),
143.06 (C2), 144.11 (Carom), 144.99 (Carom), 153.34
(C9a), 156.74 (C5), 157.08 (C3a). Mass spectrum:
N-(Morpholin-4-ylmethylidene)-5-[4-(4-nitro-
phenylsulfanylmethyl)-4,5-dihydro-1,3-thiazol-2-
yl]-1H-imidazol-4-amine (Xc). Yield 0.34 g (79%),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 1 2013

SYNTHESIS OF 7-IODO(ARYLSULFANYL)METHYL-7,8-DIHYDRO[1,3]THIAZOLO...
129
mp 140–142°C. IR spectrum, ν, cm–1: 1620, 1590,
6. Kunes, J., Bazant, J., Pour, M., Waissel, K., Slosa-
rek, M., and Janota, J., Farmaco, 2000, vol. 55, p. 725.
1490, 1440, 1390, 1330, 1290, 1230, 1190, 1110, 1090,
1
7. Xu, G.F., Song, B.A., Bhadury, P.S., Yang, S.,
Zhang, P.Q., Jin, L.H., Xue, W., Hu, D.Y., and Lu, P.,
Bioorg. Med. Chem., 2007, vol. 15, p. 3768.
8. Koppel, H.C., O’Brien, D.E., and Robins, R.K., J. Org.
Chem., 1959, vol. 24, p. 259.
1030, 940. H NMR spectrum, δ, ppm: 3.04–3.18 m
(2H, CH2), 3.31–3.48 m (4H, CH2), 3.63 m (6H, CH2),
4.70–4.79 m (1H, CH), 7.46 (1H, N=CH), 7.58 d (2H,
H
arom, J = 8.7 Hz), 8.13 d (2H, Harom, J = 8.7 Hz),
8.13 s (1H, 2-H), 12.23 s (1H, NH). 13C NMR spec-
trum, δC, ppm: 36.07 (C5′), 36.65 (4′-CH2), 43.25
(NCH2), 49.03 (NCH2), 66.01 (OCH2), 67.13 (OCH2),
73.61 (C4′), 112.96 (C4), 124.35 (2C, Carom), 126.97
(2C, Carom), 136.28 (C2), 144.93 (Carom), 148.07 (Carom),
151.64 (C5), 152.52 (N=CH), 157.01 (C2′). Found, %:
C 49.83; H 4.61; N 19.36; S 14.75. C18H20N6O3S2. Cal-
culated, %: C 49.99; H 4.66; N 19.43; S 14.83.
9. Coulthard, S. and Hogarth, L., Invest. New Drugs, 2005,
vol. 23, p. 523.
10. Miron, T., Arditti, F., Konstantinovski, L., Rabinkov, A.,
Milerman, D., Berrebi, A., and Wilchek, M., Eur. J.
Med. Chem., 2009, vol. 44, p. 541.
11. Gunnarsdottir, S. and Elfarra, A.A., J. Pharmacol. Exp.
Ther., 1999, vol. 290, p. 950.
12. Balsiger, R.W., Fikes, A.L., Johnston, T.P., and Mon-
thomery, J.A., J. Org. Chem., 1961, vol. 26, p. 3446.
13. Monthomery, J.A., Balsiger, R.W., Fikes, A.L., and
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