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

Article abstract of DOI:10.1134/S1070428010050167

The protection of the 7-NH group in 8-bromo-3-methyl-3,7-dihydro-1H-pyrine- 2,6-dione during the synthesis of 7-ubsubstituted 1-alkyl-8-bromo-3-methyl-3,7- dihydro-1H-pyrine-2,6-diones with a thienyl group was applied that was introduced by the reaction with 2-chloromethylthiirane. The thietanyl protection was removed by treating with sodium alcoholate after the oxidation with hydrogen peroxide to thietane 1,1-dioxide group. Pleiades Publishing, Ltd., 2010.

Full text of DOI:10.1134/S1070428010050167

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 5, pp. 689−692. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © F.A. Khaliullin, Yu.V. Shabalina, R.M. Sharafutdinov, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46,
No. 5, pp. 698−701.
Thietanyl Protection in the Synthesis
of 1-Alkyl-8-bromo-3-methyl-3,7-dihydro-1H-purine-2,6-diones
F.A. Khaliullin, Yu. V. Shabalina, and R. M. Sharafutdinov
Bashkir State Medical University, Ufa, 450000 Russia
e-mail: khaliullin_ufa@yahoo.com
Received July 27, 2009
Abstract—The protection of the 7-NH group in 8-bromo-3-methyl-3,7-dihydro-1H-pyrine-2,6-dione during the
synthesis of 7-ubsubstituted 1-alkyl-8-bromo-3-methyl-3,7-dihydro-1H-pyrine-2,6-diones with a thienyl group
was applied that was introduced by the reaction with 2-chloromethylthiirane. The thietanyl protection was removed
by treating with sodium alcoholate after the oxidation with hydrogen peroxide to thietane 1,1-dioxide group.
DOI: 10.1134/S1070428010050167
7
1
-Substituted 8-halo-3-methyl-3,7-dihydro-1H-pyrine-
The thietane ring in the position N was introduced by
reacting the 8-bromo-3-methyl-3,7-dihydro-1H-pyrine-
2,6-dione with 2-chloromethylthiirane. The 8-bromo-3-
methyl-7-(thietan-3-yl)-3,7-dihydro-1H-pyrine-2,6-dione
(I) formed as a result of the thiirane-thietane rearrange-
ment [5] (Scheme 1).
2
7
,6-diones are used in the preparation of biologically active
,8-disubstituted or fused by the f side pyrine-2,6-dione
derivatives [1, 2]. However their synthesis by the direct
alkylation of 8-halo-3-methyl-3,7-dihydro-1H-pyrine-2,6-
diones at the position N is impossible because of the
1
high reactivity of the 7-NH group [3]. We used for block-
ing the 7-NH group in the synthesis of 1-alkyl-8-bromo-
The alkylation of the thietanylpyrinedione (I) into the
position N was carried out with alkyl halides in DMF in
1
3
-methyl-3,7-dihydro-1H-pyrine-2,6-diones a new
the presence of potassium hydroxide. 1-Alkyl-8-bromo-
protective group, a thietane ring [4].
3-methyl-7-(thietan-3-yl)-3,7-dihydro-1H-pyrine-2,6-
Scheme 1.
O
O
Cl
HN
NH
Br
S
HN
N
S
KOH, H O
O
N
N
2
O
N
N
Br
CH3
CH3
I
Scheme 2.
O
O
N
HN
N
S
R N
O
N
S
KOH
DMF
+
R Hlg
O
N
N
Br
N
Br
CH3
CH3
_
I
IIa IIf
R = Me (a), Et (b), Pr (c), Bu (d), C H (e), C H (f); Hlg = Br, I.
5
11
6
13
689

690
KHALIULLIN et al.
diones IIa–IIf formed in 66–88% yields (Scheme 2).
medium of the corresponding alcohol. Unsubstituted at
the position N 1-alkyl-8-bromo-3-methyl-3,7-dihydro-1H-
pyrine-2,6-diones IVa–IVf were obtained in 70–87%
yields. 3-Alkoxythietane 1,1-dioxides Va, Vb were
isolated in 63–94% yields (Scheme 4).
7
Compound IIa melted without depression of the melting
point in the mixed sample with the substance obtained by
alkylation of 8-bromo-1,3-dimethyl-3,7-dihydro-1H-pyrine-
2,6-dione with 2-chloromethylthiirane [5].
1H NMR spectra of the alkylated compounds contain-
The characteristics of compound IVa were consistent
with the published data [6].
ed the multiplets from the protons of the thietane ring in
the ranges 3.2–3.4 [S(CH) ], 4.3–4.5 [S(CH) ], and 5.9–
1
2
2
In the H NMR spectra of 7-unsubstituted compounds
6
.1 ppm (NCH), and also a singlet from the 3-methyl and
were absent the proton signals of the thietane 1,1-dioxide
13
signals from 1-alkyl substituents. The C NMR spectrum
of compound IIb confirms the presence of the 1-ethyl
substituent by the signal of carbon atoms at 13.11 (CH3)
and 37.07 ppm (1-CH2).
ring. The IR spectrum of compound IVb contained the
7
band of the stretching vibrations of N –H bond at
–1
3048 cm .
Hence the application of the thietanyl protection made
it possible to successfully synthesize difficultly accessible
To remove the thietanyl protection compounds IIa–
IIf were oxidized with excess hydrogen peroxide in acetic
acid to the formation of 1-alkyl-8-bromo-3-methyl-7-(1,1-
dioxothietan-3-yl)-3,7-dihydro-1H-pyrine-2,6-diones IIIa–
IIIf (Scheme 3). The yield of compounds IIIa–IIIf was
7
1
-unsubstituted 1-alkyl-8-bromo-3-methyl-3,7-dihydro-
H-pyrine-2,6-diones.
EXPERIMENTAL
4
4–68%.
1
In the H NMR spectra of the oxidized compounds
the proton signals of two S(CH) groups of the thietane
1
IR spectra of compounds obtained were recorded on
a spectrophotometer Specord M-80 from mulls in mineral
2
1
13
,1-dioxide ring were shifted downfield with respect to
their position in the spectrum of thietane ring by 0.6–
.3 ppm. The IR spectra of compounds IIIa, IIIb
contained strong absorption bands of the stretching
vibrations of the SO group in the region 1126–1140 and
oil. H and C NMR spectra were registered on
a spectrometer BrukerAM-300 at operating frequencies
1
13
1
300 ( H) and 75 MHz ( C). The solvent signals served
as internal reference. The homogeneity of compounds
synthesized was checked by TLC on Silufol plates (eluents
chloroform–ethanol, 1 : 3, or 1-butanol–acetic acid–water,
2
–1
1
312–1320 cm .
4
: 1 : 2, development in iodine vapor).
Thietane 1,1-dioxide ring was removed by the reaction
of compounds IIIa–IIIf with sodium alcoholates in the
Compound I was obtained by procedure [5]. Synthesis
Scheme 3.
O
O
O
O
H O
R N
O
N
S
2
2
R N
O
N
S
CH COOH
3
N
N
Br
N
N
Br
CH3
CH3
_
_
IIa IIf
IIIa IIIf
Scheme 4.
O
O
O
O
O
O
R N
O
N
N
S
R' ONa
R'OH
R N
NH
+
R'O
S
N
Br
O
N
N
Br
CH3
CH3
_
_
IIIa IIIf
IVa IVf
Va, Vb
R' = Et (a), i-Pr (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 5 2010

THIETANYL PROTECTION IN THE SYNTHESIS
691
of compounds IIa, IIc, IIIc, IVc, Va, Vc was described
diluted with 6 ml of water. The precipitate was filtered
in [4].
off, washed with water, and dried. Yield 82%, mp 137–
1
1
0
1
3
4
38°C (ethanol). H NMR spectrum (CDCl ), δ, ppm:
1
-Alkyl-8-bromo-3-methyl-7-(thietan-3-yl)-3,7-
3
.88 t (3H, CH , J 6.9 Hz), 1.24–1.43 m [6H, (CH ) ],
dihydro-1H-pyrine-2,6-diones IIa–IIf. To a mixture
of 3.17 g (10 mmol) of compound I and 80 ml of DMF
was added a solution of 0.67 g (12 mmol) of potassium
hydroxide in 4 ml of water, 12 mmol of alkyl bromide
3
2 3
.60–1.72 m (2H, CH ), 3.27–3.37 m [2H, S(CH) ],
2
2
.55 s (3H, 3-CH ), 4.01–4.09 m (2H, 1-CH ), 4.36–
3
2
.46 m [2H, S(CH) ], 5.95–6.09 m (1H, NCH). Found,
2
%
: C 45.04; H 5.44; N 13.89. C H BrN O S.
(
IIe) or iodide (IIa–IId, IIf), and the mixture was stirred
15 21 4 2
Calculated, %: C 44.89; H 5.27; N 13.96.
at room temperature for 4 h. The reaction mixture was
diluted with 25 ml of water, the precipitate was filtered
off, washed with water, and dried.
1-Alkyl-8-bromo-3-methyl-7-(1,1-dioxothietan-
3-yl)-3,7-dihydro-1H-pyrine-2,6-diones IIIa–IIIf. In
2
5 ml of acetic acid was dissolved at heating 5 mmol of
8
-Bromo-3-methyl-7-(thietan-3-yl)-1-ethyl-3,7-
an appropriate compound IIa–IIf, 5.67 g (50 mmol) of
30% hydrogen peroxide solution was added, and the
mixture was boiled for 30 min. On cooling 25 ml of water
was added. The precipitate was filtered off, washed with
water, and dried.
dihydro-1H-pyrine-2,6-dione (IIb). Yield 88%, mp
1
2
23–225°C (ethanol). H NMR spectrum (CDCl ), δ,
3
ppm: 1.24 t (3H, CH , J 7.0 Hz), 3.23–3.34 m [2H,
3
S(CH) ], 3.51 s (3H, 3-CH ), 4.10 q (2H, 1-CH ,
2
3
2
J 7.0 Hz), 4.31–4.42 m [2H, S(CH) ], 5.90–6.06 m (1H,
2
NCH). 13C NMR spectrum (CDCl ), δ, ppm: 13.11
8-Bromo-1,3-dimethyl-7-(1,1-dioxothietan-3-yl)-
3
(
5
1
CH ), 29.75 (3-CH ), 34.80 [S(CH ) ], 37.07 (1-CH ),
3,7-dihydro-1H-pyrine-2,6-dione (IIIa). Yield 68%,
3
3
2 2
2
2
5
4
–1
2.92 (NCH), 109.26 (C ), 126.63 (C ), 149.01 (C ),
mp 305°C (decomp.) (DMF). IR spectrum, ν, cm : 1140,
6
8
50.57 (C ), 153.72 (C ). Found, %: C 38.19; H 3.67;
1320 (SO ), 1600, 1660, 1710 (C=C, C=N, C=O). Found,
2
N 16.34. C H BrN O S. Calculated, %: C 38.27;
%: C 33.34; H 3.30; N 15.70. C H BrN O S.
1
1
13
4
2
10 11
4
4
H 3.80; N 16.23.
Calculated, %: C 33.07; H 3.05; N 15.43.
8
-Bromo-1-butyl-3-methyl-7-(thietan-3-yl)-3,7-
8-Bromo-3-methyl-7-(1,1-dioxothietan-3-yl)-1-
dihydro-1H-pyrine-2,6-dione (IId). Yield 88%, mp
ethyl-3,7-dihydro-1H-pyrine-2,6-dione (IIIb). Yield
1
–1
1
55–156ºC (ethanol). H NMR spectrum (CDCl ), δ,
44%, mp 253°C (decomp.) (DMF). IR spectrum, ν, cm :
3
ppm: 0.96 t (3H, CH , J 7.3 Hz), 1.33–1.47 m (2H, CH ),
1126, 1312 (SO ), 1612, 1654, 1696 (C=C, C=N, C=O).
3
2
2
1
3
4
.59–1.71 m (2H, CH ), 3.27–3.36 m [2H, S(CH) ],
Found, %: C 35.14; H 3.64; N 14.77. C H BrN O S.
Calculated, %: C 35.03; H 3.47; N 14.85.
2
2
11 13
4
4
.55 s (3H, 3-CH ), 4.02–4.10 m (2H, 1-CH ), 4.36–
3
2
.46 m [2H, S(CH) ], 5.96–6.10 m (1H, NCH). Found,
2
8-Bromo-1-butyl-3-methyl-7-(1,1-dioxothietan-
%
: C 41.67; H 4.46; N 15.20. C H BrN O S.
13 17 4 2
3-yl)-3,7-dihydro-1H-pyrine-2,6-dione (IIId). Yield
Calculated, %: C 41.83; H 4.59; N 15.01.
1
5
2%, mp 257°C (decomp.) (ethanol). H NMR spectrum
8
-Bromo-3-methyl-1-pentyl-7-(thietan-3-yl)-3,7-
(DMF-d ), δ, ppm: 0.90 t (3H, CH , J 7.3 Hz), 1.28–
7
3
dihydro-1H-pyrine-2,6-dione (IIe). The reaction
mixture was stirred at 45°C for 4 h. On cooling 25 ml of
water was added. The precipitate was filtered off,
washed with 1% potassium hydroxide solution, with water,
and dried. Yield 77%, mp 169–170°C (ethanol). H NMR
spectrum (CDCl ), δ, ppm: 0.91 t (3H, CH , J 6.6 Hz),
.32–1.41 m [4H, (CH ) ], 1.62–1.73 m (2H, CH ), 3.28–
1.39 m (2H, CH ), 1.51–1.62 m (2H, CH ), 3.48 s (3H,
2 2
3-CH3), 4.02–4.08 m (2H, 1-CH2), 4.59–4.70 m [2H,
S(CH)2], 5.15–5.27 m [2H, S(CH)2], 5.53–5.65 m (1H,
NCH). Found, %: C 38.77; H 4.17; N 13.57.
1
C H BrN O S. Calculated, %: C 38.53; H 4.23;
13 17 4 4
N 13.82.
3
3
1
8-Bromo-3-methyl-1-pentyl-7-(1,1-dioxothietan-
2
2
2
3
.37 m [2H, S(CH) ], 3.55 s (3H, 3-CH ), 4.02–4.09 m
2
3
3-yl)-3,7-dihydro-1H-pyrine-2,6-dione (IIIe). Yield
(
(
2H, 1-CH ), 4.37–4.46 m [2H, S(CH) ], 5.96–6.10 m
1H, NCH). Found, %: C 43.70; H 5.09; N 14.20.
1
2
2
50%, mp 237–239°C (ethanol). H NMR spectrum
DMCO-d ), δ, ppm: 0.86 t (3H, CH , J 6.8 Hz), 1.21–
(
6
3
C H BrN O S. Calculated, %: C 43.42; H 4.94;
N 14.47.
1
4
19
4
2
1.34 m [4H, (CH ) ], 1.49–1.60 m (2H, CH ), 3.39 s
2 2 2
(
3H, 3-CH ), 3.83–3.90 m (2H, 1-CH ), 4.52–4.61 m
3 2
8
-Bromo-1-hexyl-3-methyl-7-(thietan-3-yl)-3,7-
[2H, S(CH) ], 4.99–5.08 m [2H, S(CH) ], 5.37–5.50 m
2
2
dihydro-1H-pyrine-2,6-dione (IIf). The reaction
mixture was stirred at room temperature for 6 h and then
(1H, NCH). Found, %: C 40.25; H 4.81; N 13.60.
C H BrN O S. Calculated, %: C 40.10; H 4.57;
1
4
19
4
4
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 5 2010

692
KHALIULLIN et al.
N 13.36.
%: C 35.19; H 3.32; N 20.52.
8
-Bromo-1-hexyl-3-methyl-7-(1,1-dioxothietan-
8-Bromo-1-butyl-3-methyl-3,7-dihydro-1H-
pyrine-2,6-dione (IVd). Yield 74%, mp 233–235°C
3
5
(
[
-yl)-3,7-dihydro-1H-pyrine-2,6-dione (IIIf). Yield
5%, mp 192–193°C (ethanol). H NMR spectrum
CDCl ), δ, ppm: 0.89 t (3H, CH , J 6.6 Hz), 1.25–1.43 m
6H, (CH ) ], 1.57–1.71 m (2H, CH ), 3.56 s (3H,
1
1
(ethanol). H NMR spectrum (DMF-d ), δ, ppm: 0.88 t
7
(3H, CH , J 7.3 Hz), 1.22–1.36 m (2H, CH ), 1.48–
3
3
3
2
1.60 m (2H, CH ), 3.47 s (3H, 3-CH ), 3.86-3.93 m (2H,
2
3
2
2 3
3
-CH ), 4.00–4.09 m (2H, 1-CH ), 4.33–4.44 m [2H,
1-CH ). Found, %: C 39.62; H 4.05; N 18.84.
3
2
2
S(CH) ], 5.21–5.32 m [2H, S(CH) ], 5.57–5.71 m (1H,
C H BrN O . Calculated, %: C 39.88; H 4.35; N 18.60.
2
2
10 13
4
2
NCH). Found, %: C 41.46; H 4.69; N 12.70.
C H BrN O S. Calculated, %: C 41.58; H 4.88;
N 12.93.
8
-Bromo-3-methyl-1-pentyl-3,7-dihydro-1H-
1
5
21
4
4
pyrine-2,6-dione (IVe). Yield 70%, mp 172–174°C
ethanol). H NMR spectrum (DMSO-d ), δ, ppm: 0.84 t
(3H, CH , J 6.6 Hz), 1.17–1.38 m [4H, (CH ) ], 1.45–
1
(
6
1
-Alkyl-8-bromo-3-methyl-3,7-dihydro-1H-
3 2 2
pyrine-2,6-diones IVa–IVf and 3-alkoxythietane 1,1-
dioxides Va, Vb. In 25 ml of ethanol (IVa, IVd, IVe)
or 2-propanol (IVb, IVc, IVf) was dissolved 0.14 g
1
1
.57 m (2H, CH ), 3.37 s (3H, 3-CH ), 3.78–3.85 m (2H,
2 3
-CH ). Found, %: C 41.66; H 4.95; N 17.98.
2
C H BrN O . Calculated, %: C 41.92; H 4.80; N 17.78.
11
15
4
2
(6 mg-at) of metal sodium. Into the solution obtained was
8
-Bromo-1-hexyl-3-methyl-3,7-dihydro-1H-
added 5 mmol of an appropriate dione IIIa–IIIf, and the
mixture was boiled for 30 min. The solvent was
evaporated in a vacuum, the residue was dissolved in
pyrine-2,6-dione (IVf). Yield 87%, mp 173–175°C
1
(
(
ethanol). H NMR spectrum (CDCl ), δ, ppm: 0.88 t
3H, CH , J 6.8 Hz), 1.24–1.46 m [6H, (CH ) ], 1.65–
3
3
2 3
1
5 ml of water and extracted with benzene (3 × 15 ml).
1
1
.78 m (2H, CH ), 3.62 s (3H, 3-CH ), 4.05–4.14 m (2H,
The water solution was neutralized with 8% HCl to pH 3.
The separated precipitate was filtered off, washed with
water, and dried to obtain compounds IVa–IVf. The
benzene extract was evaporated, the residue was dried
and recrystallized from ethanol to obtain compounds Va
and Vb.
2 3
-CH ). Found, %: C 43.58; H 5.05; N 17.22.
2
C H BrN O . Calculated, %: C 43.78; H 5.21; N 17.02.
12 17
4
2
REFERENCES
1
. Rybar,A., Adv. Heterocycl. Chem., 2004, vol. 87, p. 85.
8
-Bromo-1,3-dimethyl-3,7-dihydro-1H-pyrine-
,6-dione (IVa). Yield 85%, mp 303°C (decomp.)
DMF). The substance melted without depression of the
2. Khaliullin, F.A., Filipenko, Yu.V., Saitgalina, A.Z., Spa-
2
(
sov, A.A., and Naumenko, L.V., RF Patent 2316551, 2006;
Rossiya Byull. Izobr., 2008, no. 4.
melting point in the mixed sample with the compound
obtained by procedure [6].
3. Gulevskaya, A.V. and Pozharskii, A.F., Khim. Geterotsikl.
Soedin., 1991, p. 3.
8
-Bromo-3-methyl-1-ethyl-3,7-dihydro-1H-
4. Khaliullin, F.A. and Klen, E.E., Zh. Org. Khim., 2009, vol. 45,
pyrine-2,6-dione (IVb). Yield 80%, mp 275°C
decomp.) (ethanol). IR spectrum, ν, cm : 1608, 1636,
664, 1712 (C=C, C=N, C=O), 3048 (NH). H NMR
p. 138.
–1
(
5. Khaliullin, F.A., Kataev, V.A., and Strokin, Yu.V., Khim.
1
1
Geterotsikl. Soedin., 1991, p. 516.
spectrum (DMF-d ), δ, ppm: 1.15 t (3H, CH , J 7.0 Hz),
6. Eckstein, M., Gorczyca, M., and Zlic, A., Acta Pharm.
Iugoslav., 1972, vol. 22, p. 133; Ref. Zh. Khim., 1973, 11N,
p. 377.
7
3
3
.47 s (3H, 3-CH ), 3.96 q (2H, 1-CH , J 7.0 Hz). Found,
3 2
%
: C 35.00; H 3.16; N 20.35. C H BrN O . Calculated,
8 9 4 2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 5 2010