Thietanyl protection in the synthesis of 1-alkyl-8-amino-3-methyl-3,7-dihydro-1H-purine-2,6-diones

Article abstract of DOI:10.1134/S1070428015100139

1-Alkyl-8-bromo-3-methyl-7-(1,1-dioxo-1λ⁶-thietan-3-yl)-3,7-dihydro-1H-purine-2,6-diones reacted with amines to give the corresponding 1-alkyl-8-amino-3-methyl-7-(1,1-dioxo-1λ⁶-thietan-3-yl)-3,7-dihydro-1H-purine-2,6-diones which wer

Full text of DOI:10.1134/S1070428015100139

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 10, pp. 1434–1437. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © F.A. Khaliullin, Yu.V. Shabalina, R.M. Sharafutdinov, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 10,
pp. 1465–1468.
Thietanyl Protection in the Synthesis
of 1-Alkyl-8-amino-3-methyl-3,7-dihydro-1H-purine-2,6-diones
F. A. Khaliullin, Yu. V. Shabalina, and R. M. Sharafutdinov
Bashkir State Medical University, ul. Lenina 3, Ufa, 450000 Bashkortostan, Russia
e-mail: khaliullin_ufa@yahoo.com
Received May 22, 2015
Abstract—1-Alkyl-8-bromo-3-methyl-7-(1,1-dioxo-1λ6-thietan-3-yl)-3,7-dihydro-1H-purine-2,6-diones react-
ed with amines to give the corresponding 1-alkyl-8-amino-3-methyl-7-(1,1-dioxo-1λ6-thietan-3-yl)-3,7-dihy-
dro-1H-purine-2,6-diones which were treated with sodium alkoxide to remove thietanyl protecting group with
formation of 1-alkyl-8-amino-3-methyl-3,7-dihydro-1H-purine-2,6-diones possessing no substituent on N7.
DOI: 10.1134/S1070428015100139
We previously described [1] the use of thietanyl
protecting group in the synthesis of 7-unsubstituted
1-alkyl-8-bromo-3-methyl-3,7-dihydro-1H-purine-2,6-
diones. In this work we followed an analogous ap-
proach to synthesize 1-alkyl-8-amino-3-methyl-3,7-di-
hydro-1H-purine-2,6-diones having no substituent on
N7. These compounds are difficultly accessible since
direct alkylation of N1 in 8-substituted 3-methyl-3,7-
dihydro-1H-purine-2,6-diones is impossible due to
higher reactivity of N7 [2]. Moreover, 7-unsubstituted
1-alkyl-8-halo-3-methyl-3,7-dihydro-1H-purine-2,6-
diones react with amines only under harsh conditions
(under pressure or using the amine as reaction
medium) [3]. Both these difficulties could be over-
come by blocking the 7-position with a thietanyl
protecting group.
oxidation of the thietane ring to thietane 1,1-dioxide.
The reactions of 1a–1d with amines were carried out
by heating the reactants in boiling ethanol or DMF for
1–5 h. The corresponding 8-amino derivatives 2a–2h
were formed in 76–91% yield (Scheme 1).
1
The H NMR spectra of 2a–2h contained signals
from protons in the alkyl substituents on N1 and N3,
multiplet signals typical of thietane 1,1-dioxide ring,
and signal of the corresponding amine residues in the
8-position. For example, compound 2c displayed
multiplets at δ 3.15–3.23 and 3.83–3.91 ppm due to
CH2NCH2 and CH2OCH2 protons in the morpholine
fragment. In the IR spectra of 2a–2h we observed
strong absorption bands due to stretching vibrations of
sulfonyl group at 1133–1148 and 1309–1321 cm–1.
The thietane protection was removed by treatment
of 2a–2h with sodium ethoxide or isopropoxide in the
corresponding alcohol (30 min under reflux). 1-Alkyl-
8-amino-3-methyl-3,7-dihydro-1H-purine-2,6-diones
3a–3h were thus isolated in 59–98% yield, and the
Initial 1-alkyl-8-bromo-3-methyl-7-(1,1-dioxo-1λ6-
thietan-3-yl)-3,7-dihydro-1H-purine-2,6-diones 1a–1d
were synthesized as described in [1] via introduction of
a thietanyl protecting group, alkylation of N1, and
Scheme 1.
O
O
O
O
O
Alk
Alk
S
S
R3ONa
R3OH
H
N
O
O
Alk
O
O
O
R1R2NH
N
N
N
N
NR1R2
+
R3O
S
O
N
O
N
N
N
N
N
Br
N
NR1R2
Me
Me
Me
1a–1d
2a–2h
3a–3h
4a, 4b
1, Alk = Et (a), Pr (b), Bu (c), C5H11 (d); 2, 3, Alk = Et, R1 = H, R2 = PhCH2 (a); Alk = Pr, R1R2N = piperidin-1-yl (b), morpholin-
4-yl (c), azepan-1-yl (d); Alk = Bu, R1R2N = piperidin-1-yl (e), morpholin-4-yl (f); Alk = C5H11, piperidin-1-yl (g), morpholin-
4-yl (h); 4, R3 = Et (a), i-Pr (b).
1434

THIETANYL PROTECTION IN THE SYNTHESIS OF 1-ALKYL-8-AMINO-...
1435
yield of the other product, 3-alkoxy-1λ6-thietane
1,1-dioxide 4a or 4b ranged from 84 to 94%. The
properties of the latter were consistent with published
data [4].
a solution of 1.56 g (4 mmol) of compound 1b in
35 mL of ethanol, and the mixture was heated for 5 h
under reflux. The mixture was cooled, and the precip-
itate was filtered off, washed with water, and dried.
Yield 1.20 g (76%), mp 204–205°C (from EtOH). IR
spectrum, ν, cm–1: 1703, 1643, 1604, (C=C, C=N,
1
The H NMR spectra of 3a–3h showed signals be-
longing to alkyl substituents on N1 and N3 and amine
residues on C8 and a singlet at δ 11.15–11.88 ppm due
to N7H, while no signals assignable to thietane 1,1-di-
oxide ring were present. The N7–H stretching vibration
band was observed in the region 3000–3300 cm–1 of
the IR spectra of 3a–3h.
1
C=O), 1319, 1134 (SO2). H NMR spectrum, δ, ppm:
0.94 t (3H, CH3, J = 7.4 Hz), 1.62–1.77 m [8H, CH2,
(CH2)3], 3.12–3.16 m [4H, N(CH2)2], 3.52 s (3H,
3-CH3), 3.97–4.01 m (2H, 1-CH2), 4.26–4.31 m (2H,
SCH2), 5.07–5.22 m (3H, SCH2, 7-CH]. Found, %:
C 51.49; H 6.47; N 17.74. C17H25N5O4S. Calculated,
%: C 51.63; H 6.37; N 17.71.
Thus, thietanyl protection of N7 ensures successful
synthesis of difficultly accessible 1-alkyl-8-amino-3-
methyl-3,7-dihydro-1H-purine-2,6-diones having no
substituent on N7.
Compounds 2c–2h were synthesized in a similar
way.
7-(1,1-Dioxo-1λ6-thietan-3-yl)-3-methyl-8-(mor-
pholin-4-yl)-1-propyl-3,7-dihydro-1H-purine-2,6-di-
one (2c). Yield 82%, mp 234–236°C (from EtOH).
IR spectrum, ν, cm–1: 1710, 1691, 1667, 1614 (C=C,
EXPERIMENTAL
The IR spectra were recorded in KBr on
an Infralyum FT-02 spectrometer. The 1H NMR spectra
were measured on Bruker AM-300 (2a, 2c–2h) and
Bruker AM-500 spectrometers (2b) at 300 and
500 MHz respectively, using the residual proton signal
of the deuterated solvent as reference. The purity of the
isolated compounds was checked by TLC on Silufol
plates (butan-1-ol–acetic acid–water, 4:1:2; develop-
ment with iodine vapor).
1
C=N, C=O), 1139, 1317 (SO2). H NMR spectrum, δ,
ppm: 0.94 t (3H, CH3, J = 7.4 Hz), 1.59–1.74 m (2H,
CH2), 3.15–3.23 m [4H, N(CH2)2], 3.53 s (3H, 3-CH3),
3.83–3.91 m [4H, O(CH2)2], 3.96–4.05 m (2H, 1-CH2),
4.25–4.37 m (2H, SCH2), 5.12–5.28 m (3H, SCH2,
7-CH). Found, %: C 48.68; H 5.91; N 17.40.
C16H23N5O5S. Calculated, %: C 48.35; H 5.83; N 17.62.
8-(Azepan-1-yl)-7-(1,1-dioxo-1λ6-thietan-3-yl)-3-
methyl-1-propyl-3,7-dihydro-1H-purine-2,6-dione
(2d). Yield 77%, mp 199–201°C (from EtOH). IR
spectrum, ν, cm–1: 1695, 1647, 1605 (C=C, C=N,
Compounds 1a, 1c, 1d [1], 1b, 4a, and 4b [4] were
synthesized according to known methods.
8-(Benzylamino)-7-(1,1-dioxo-1λ6-thietan-3-yl)-
1-ethyl-3-methyl-3,7-dihydro-1H-purine-2,6-dione
(2a). Benzylamine, 0.96 g (9 mmol), was added to
a solution of 1.13 g (3 mmol) of compound 1a in
25 mL of DMF, and the mixture was heated for 1 h
under reflux. The mixture was cooled and diluted with
50 mL of water, and the precipitate was filtered off,
washed with water, dried, and recrystallized from
ethanol. Yield 1.10 g (91%), mp 232–234°C. IR spec-
trum, ν, cm–1: 1690, 1646, 1613 (C=C, C=N, C=O),
1
C=O), 1321, 1135 (SO2). H NMR spectrum, δ, ppm:
0.95 t (3H, CH3, J = 7.4 Hz), 1.61–1.92 m [10H, CH2,
(CH2)4], 3.42–3.48 m [4H, N(CH2)2], 3.51 s (3H,
3-CH3), 3.95–4.03 m (2H, 1-CH2), 4.18–4.28 m (2H,
SCH2), 4.98–5.12 m (1H, 7-CH), 5.16–5.26 m (2H,
SCH2). Found, %: C 52.69; H 6.37; N 17.24.
C18H27N5O4S. Calculated, %: C 52.79; H 6.65; N 17.10.
1-Butyl-7-(1,1-dioxo-1λ6-thietan-3-yl)-3-methyl-
8-(piperidin-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(2e) was synthesized from compound 1c. Yield 78%,
mp 191–193°C (from EtOH). IR spectrum, ν, cm–1:
1694, 1655, 1611 (C=C, C=N, C=O), 1309, 1133
(SO2). 1H NMR spectrum, δ, ppm: 0.95 t (3H, CH3, J =
7.3 Hz), 1.32–1.46 m (2H, CH2), 1.57–1.81 m [8H,
CH2, (CH2)3], 3.11–3.19 m [4H, N(CH2)2], 3.53 s (3H,
3-CH3), 4.00–4.08 m (2H, 1-CH2), 4.25–4.35 m (2H,
SCH2), 5.06–5.26 m (3H, SCH2, 7-CH). Found, %:
C 52.91; H 6.68; N 17.32. C18H27N5O4S. Calculated,
%: C 52.79; H 6.65; N 17.10.
1
1133, 1311 (SO2). H NMR spectrum, δ, ppm: 1.22 t
(3H, CH3, J = 7.0 Hz), 3.52 s (3H, 3-CH3), 4.05 q (2H,
CH2CH3, J = 7.0 Hz), 4.46–4.56 m (2H, SCH2), 4.67 d
(2H, PhCH2, J = 5.1 Hz), 4.84–4.94 m (CH2S), 5.69–
5.82 m (1H, 7-CH), 6.00 t (1H, NH, J = 5.1 Hz), 7.27–
7.45 m (5H, C6H5). Found, %: C 53.79; H 5.47;
N 17.54. C18H21N5O4S. Calculated, %: C 53.59;
H 5.25; N 17.36.
7-(1,1-Dioxo-1λ6-thietan-3-yl)-3-methyl-8-(piper-
idin-1-yl)-1-propyl-3,7-dihydro-1H-purine-2,6-di-
one (2b). Piperidine, 1.02 g (12 mmol), was added to
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 10 2015

KHALIULLIN et al.
1-Butyl-7-(1,1-dioxo-1λ6-thietan-3-yl)-3-methyl-
1436
8-(Benzylamino)-1-ethyl-3-methyl-3,7-dihydro-
1H-purine-2,6-dione (3a). Yield 72%, mp 233–235°C
(from EtOH). IR spectrum, ν, cm–1: 3400–3000 (NH),
8-(morpholin-4-yl)-3,7-dihydro-1H-purine-2,6-di-
one (2f) was synthesized from compound 1c. Yield
90%, mp 203–205°C (from EtOH). IR spectrum, ν,
cm–1: 1699, 1662, 1613 (C=C, C=N, C=O), 1320, 1138
(SO2). 1H NMR spectrum, δ, ppm: 0.92 t (3H, CH3, J =
7.3 Hz), 1.29–1.42 m (2H, CH2), 1.55–1.66 m (2H,
CH2), 3.15–3.24 m [4H, N(CH2)2], 3.52 s (3H, 3-CH3),
3.83–3.91 m [4H, O(CH2)2], 3.97–4.06 m (2H, 1-CH2),
4.25–4.39 m (2H, SCH2), 5.12–5.27 m (3H, SCH2,
7-CH). Found, %: C 49.82; H 6.29; N 17.10.
C17H25N5O5S. Calculated, %: C 49.62; H 6.12; N 17.02.
7-(1,1-Dioxo-1λ6-thietan-3-yl)-3-methyl-1-pentyl-
8-(piperidin-1-yl)-3,7-dihydro-1H-purine-2,6-dione
(2g) was synthesized from compound 1d. Yield 85%,
mp 177–179°C (from EtOH). IR spectrum, ν, cm–1:
1699, 1655, 1615 (C=C, C=N, C=O), 1317, 1148
(SO2). 1H NMR spectrum, δ, ppm: 0.90 t (3H, CH3, J =
6.3 Hz), 1.28–1.40 m [4H, (CH2)2], 1.57–1.81 m [8H,
CH2, (CH2)3], 3.09–3.18 m [4H, N(CH2)2], 3.53 s (3H,
3-CH3), 3.97–4.06 m (2H, 1-CH2), 4.24–4.35 m (2H,
SCH2), 5.07–5.26 m (3H, SCH2, 7-CH). Found, %:
C 53.97; H 6.78; N 16.38. C19H29N5O4S. Calculated,
%: C 53.88; H 6.90; N 16.54.
7-(1,1-Dioxo-1λ6-thietan-3-yl)-3-methyl-8-(mor-
pholin-4-yl)-1-pentyl-3,7-dihydro-1H-purine-2,6-di-
one (2h) was synthesized from compound 1d. Yield
80%, mp 163–165°C (from EtOH). IR spectrum, ν,
cm–1: 1698, 1655, 1610 (C=C, C=N, C=O), 1313, 1142
(SO2). 1H NMR spectrum, δ, ppm: 0.89 t (3H, CH3, J =
6.4 Hz), 1.18–1.40 m [4H, (CH2)2], 1.57–1.69 m (2H,
CH2), 3.15–3.23 m [4H, N(CH2)2], 3.53 s (3H, 3-CH3),
3.83–3.91 m [4H, O(CH2)2], 3.97–4.06 m (2H, 1-CH2),
4.24–4.39 m (2H, SCH2), 5.13–5.28 m (3H, SCH2,
7-CH). Found, %: C 51.02; H 6.29; N 16.39.
C18H27N5O5S. Calculated, %: C 50.81; H 6.40; N 16.46.
1
1698, 1655, 1629 (C=C, C=N, C=O). H NMR spec-
trum, δ, ppm: 1.10 t (3H, CH3, J = 7.0 Hz), 3.53 s (3H,
3-CH3), 3.94 q (2H, 1-CH2, J = 7.0 Hz), 4.70 d (2H,
CH2, J = 5.9 Hz), 5.24 t (1H, 8-NH, J = 5.9 Hz), 7.18–
7.37 m (5H, C6H5), 11.88 s (1H, 7-H). Found, %:
C 59.89; H 5.57; N 23.57. C15H17N5O2. Calculated, %:
C 60.19; H 5.72; N 23.40.
3-Methyl-8-(piperidin-1-yl)-1-propyl-3,7-dihy-
dro-1H-purine-2,6-dione (3b). Yield 59%, mp 261–
263°C (from EtOH). IR spectrum, ν, cm–1: 3300–3000
1
(NH), 1699, 1653, 1615 (C=C, C=N, C=O). H NMR
spectrum, δ, ppm: 0.94 t (3H, CH3, J = 7.4 Hz), 1.62–
1.74 m [8H, CH2, (CH2)3], 3.54 s (3H, 3-CH3), 3.61–
3.69 br.s [4H, N(CH2)2], 3.89–3.98 m (2H, 1-CH2),
11.46 s (1H, 7-H). Found, %: C 57.52; H 7.47;
N 23.88. C14H21N5O2. Calculated, %: C 57.71; H 7.27;
N 24.04.
3-Methyl-8-(morpholin-4-yl)-1-propyl-3,7-dihy-
dro-1H-purine-2,6-dione (3c). Yield 63%, mp 317–
319°C (from EtOH. IR spectrum, ν, cm–1: 3300–3050
1
(NH), 1703, 1656, 1627 (C=C, C=N, C=O). H NMR
spectrum, δ, ppm: 0.96 t (3H, CH3, J = 7.4 Hz), 1.60–
1.74 m (2H, CH2), 3.55 s (3H, 3-CH3), 3.67–3.76 m
[4H, N(CH2)2], 3.78–3.87 m [4H, O(CH2)2], 3.88–
3.96 m (2H, 1-CH2), 11.68 s (1H, 7-H). Found, %:
C 53.28; H 6.29; N 23.72. C13H19N5O3. Calculated, %:
C 53.23; H 6.53; N 23.88.
8-(Azepan-1-yl)-3-methyl-1-propyl-3,7-dihydro-
1H-purine-2,6-dione (3d). Yield 67%, mp 243–244°C
(from EtOH). IR spectrum, ν, cm–1: 3300–3050 (NH),
1
1705, 1663, 1624 (C=C, C=N, C=O). H NMR spec-
trum, δ, ppm: 0.94 t (3H, CH3, J = 7.4 Hz), 1.52–
1.88 m [10H, CH2, (CH2)4], 3.65–3.76 m [4H,
N(CH2)2], 3.55 s (3H, 3-CH3), 3.88–3.97 m (2H,
1-CH2), 11.15 s (1H, 7-H). Found, %: C 59.29; H 7.47;
N 23.04. C15H23N5O2. Calculated, %: C 59.00; H 7.59;
N 22.93.
1-Alkyl-8-amino-3-methyl-3,7-dihydro-1H-pu-
rine-2,6-diones 3a–3h and 3-alkoxy-1λ6-thietane
1,1-dioxides 4a and 4b (general procedure). Metallic
sodium, 0.14 g (6 mmol), was dissolved in 25 mL of
ethanol or propan-2-ol, 5 mmol of compound 2b, 2c,
or 2e–2h (EtOH) or 2a or 2d (i-PrOH) was added, and
the mixture was heated for 30 min under reflux. The
mixture was evaporated under reduced pressure, the
residue was dissolved in 15 mL of water, and the
solution was extracted with benzene (3×15 mL). The
aqueous phase was adjusted to pH 3 by adding
8% aqueous HCl, and the precipitate (compound 3a–
3h) was filtered off, washed with water, and dried. The
benzene extract was evaporated, and the residue (com-
pound 4a or 4b) was dried.
1-Butyl-3-methyl-8-(piperidin-1-yl)-3,7-dihydro-
1H-purine-2,6-dione (3e). Yield 85%, mp 231–233°C
(from EtOH). IR spectrum, ν, cm–1: 3300–3050 (NH),
1
1701, 1653, 1622 (C=C, C=N, C=O). H NMR spec-
trum, δ, ppm: 0.94 t (3H, CH3, J = 7.3 Hz), 1.29–
1.43 m (2H, CH2), 1.57–1.72 m [8H, CH2, (CH2)3],
3.55 s (3H, 3-CH3), 3.61–3.68 br.s [4H, N(CH2)2],
3.94–4.02 m (2H, 1-CH2), 11.43 s (1H, 7-H). Found,
%: C 59.22; H 7.73; N 22.84. C15H23N5O2. Calculated,
%: C 59.00; H 7.59; N 22.93.
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THIETANYL PROTECTION IN THE SYNTHESIS OF 1-ALKYL-8-AMINO-...
1437
3-Methyl-8-(morpholin-4-yl)-1-pentyl-3,7-dihy-
dro-1H-purine-2,6-dione (3h). Yield 86%, mp 243–
245°C (from EtOH). IR spectrum, ν, cm–1: 3300–3050
1-Butyl-3-methyl-8-(morpholin-4-yl)-3,7-dihy-
dro-1H-purine-2,6-dione (3f). Yield 98%, mp 263–
265°C (from EtOH). IR spectrum, ν, cm–1: 3230–3050
1
1
(NH), 1706, 1650, 1624 (C=C, C=N, C=O). H NMR
(NH), 1703, 1651, 1620 (C=C, C=N, C=O). H NMR
spectrum, δ, ppm: 0.90 t (3H, CH3, J = 6.6 Hz), 1.24–
1.43 m [4H, (CH2)2], 1.57–1.69 m (2H, CH2), 3.55 s
(3H, 3-CH3), 3.67–3.76 m [4H, N(CH2)2], 3.78–3.87 m
[4H, O(CH2)2], 3.89–3.98 m (2H, 1-CH2), 11.66 s
(1H, 7-H). Found, %: C 56.04; H 6.99; N 22.02.
C15H23N5O3. Calculated, %: C 56.06; H 7.21; N 21.79.
spectrum, δ, ppm: 0.95 t (3H, CH3, J = 7.3 Hz), 1.29–
1.43 m (2H, CH2), 1.54–1.68 m (2H, CH2), 3.55 s (3H,
3-CH3), 3.66–3.75 m [4H, N(CH2)2], 3.77–3.86 m
[4H, O(CH2)2], 3.89–3.98 m (2H, 1-CH2), 11.70 s
(1H, 7-H). Found, %: C 54.82; H 6.69; N 22.72.
C14H21N5O3. Calculated, %: C 54.71; H 6.89; N 22.79.
3-Methyl-1-pentyl-8-(piperidin-1-yl)-3,7-dihy-
dro-1H-purine-2,6-dione (3g). Yield 85%, mp 218–
219°C (from EtOH). IR spectrum, ν, cm–1: 3300–3100
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1
(NH), 1700, 1656, 1624 (C=C, C=N, C=O). H NMR
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3.54 s (3H, 3-CH3), 3.60–3.70 br.s [4H, N(CH2)2],
3.92–4.01 m (2H, 1-CH2), 11.39 s (1H, 7-H). Found,
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