Thietane ring as a novel protecting group

Article abstract of DOI:10.1134/S1070428009010187

A novel protecting group for NH functionality of heterocycles, a thietane ring, was proposed. It can be readily introduced by alkylation of NH-heterocycles with 2-chloromethylthiirane. Removal of the thietane protecting group is performed via oxidation to thietane 1,1-dioxide with hydrogen peroxide in acetic acid and subsequent treatment with sodium alkoxide.

Full text of DOI:10.1134/S1070428009010187

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 1, pp. 135–138. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © F.A. Khaliullin, E.E. Klen, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 1, pp. 138–141.
Thietane Ring as a Novel Protecting Group
F. A. Khaliullin and E. E. Klen
Bashkir State Medical University, ul. Lenina 3, Ufa, 450000 Bashkortostan, Russia
e-mail: klen_elena@yahoo.com
Received February 18, 2008
Abstract—A novel protecting group for NH functionality of heterocycles, a thietane ring, was proposed. It can
be readily introduced by alkylation of NH-heterocycles with 2-chloromethylthiirane. Removal of the thietane
protecting group is performed via oxidation to thietane 1,1-dioxide with hydrogen peroxide in acetic acid and
subsequent treatment with sodium alkoxide.
DOI: 10.1134/S1070428009010187
Protecting groups are widely used in many fields of
modern organic chemistry, specifically for selective
modification of particular functional groups in hetero-
cyclic compounds. For example, the 7-NH group in
xanthines is protected with a benzyl group [1], and the
1-NH group in 1,2,4-triazoles, with an 3-oxobutyl [2],
benzyl [3], or diphenylmethyl group [4].
atom (Scheme 2). Nucleophilic substitution of halogen
atoms as readily departing groups by amines was also
studied, and amino-substituted N-(thietan-3-yl)xan-
thines [8] and N-(thietan-3-yl)benzimidazoles [9] were
thus obtained (Scheme 2).
Scheme 2.
Br
N
We propose to protect NH functionality in hetero-
cycles via introduction of a thietane ring by alkylation
with 2-chloromethylthiirane in aqueous medium in the
presence of alkali. The reaction is accompanied by
thiirane–thietane rearrangement with formation of the
corresponding N-(thietan-3-yl)-substituted heterocycle
IIa–IId [5, 6] (Scheme 1).
RONa
N
S
N
OR
IIe, IIf
S
O
HNR1R2
Me
O
N
S
Ht
N
Scheme 1.
NR1R2
KOH, H2O
N
S
IIa, IIc, IId
N
Cl
Ht
H
+
S
Ht
S
Me
Ia–Id
IIa–IId
I, II, Ht = 3,5-dibromo-1H-1,2,4-triazol-1-yl (a), 8-bromo-
3-methyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl (b),
8-bromo-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-
purin-7-yl (c), 2-chloro-1H-benzimidazol-2-yl (d).
HNR1R2
N
N
NR1R2
N-(Thietan-3-yl)indoles were also reported [7].
Thietane ring is resistant to the action of acids, bases,
nucleophiles, and electrophiles, so that further mod-
ification of N-(thietan-3-yl)-substituted heterocycles
becomes possible.
II, R = Et (e), i-Pr (f).
The thietane protection does not hamper electro-
philic substitution. An example is electrophilic alkyla-
tion of 8-bromo-3-methyl-7-(thietan-3-yl)xanthine
(IIb) at the N1 atom by the action of an equimolar
amount of methyl iodide or propyl iodide in dimethyl-
formamide in the presence of potassium hydroxide
(Scheme 3). As a result, 8-bromo-1,3-dimethyl- and
For example, 3,5-dibromo-1-(thietan-3-yl)-1H-
1,2,4-triazole (IIa) reacted with sodium alkoxides to
give the corresponding 5-alkoxy derivatives IIe and IIf
as a result of nucleophilic replacement of one bromine
135

KHALIULLIN, KLEN
Thietane 1,1-dioxides are stable toward some nu-
136
Scheme 3.
cleophilic and electrophilic reagents, so that further
modification of protected heteroring may be per-
formed. For example, the reaction of 3,5-dibromo-1-
(1,1-dioxo-λ6-thietan-3-yl)-1H-1,2,4-triazole (IIIa)
with amines was not accompanied by elimination of
the thietane dioxide ring. Nucleophilic replacement of
one bromine atom leads to the formation of 5-amino-
N-(dioxothietanyl)triazoles IIIh and IIIi (Scheme 5).
Likewise, we previously synthesized 8-amino-substi-
tuted 1,3-dimethyl-7-(1,1-dioxo-λ6-thietan-3-yl)xan-
thines and 2-amino-1-(1,1-dioxo-λ6-thietan-3-yl)benz-
imidazoles [9].
S
S
O
O
R
O
N
N
N
N
RI, DMF, KOH
HN
N
Br
Br
O
N
N
Me
Me
IIb
IIc, IIg
R = Me (c), Pr (g).
8-bromo-3-methyl-1-propyl-7-(thietan-3-yl)xanthines
IIg and IIh were isolated. The physical constants of
compound IIc obtained in such a way coincided with
published data, and no depression of the melting point
was observed on mixing with a sample prepared by
alkylation of 8-bromo-1,3-dimethylxanthine with
2-chloromethylthiirane.
Thietane 1,1-dioxide ring can be removed by treat-
ment with sodium alkoxide in the corrresponding alco-
hol (Scheme 6). Presumably, the reaction is favored by
strong electron-withdrawing properties of the sulfonyl
group. The products of this reaction are 3-alkoxy-λ6-
thietane 1,1-dioxide IVa or IVb and the corresponding
heterocycle sodium salt. The latter is converted into
NH-heterocycle Ia or Id–Ii by acidification of its
aqueous solution to pH 3–4.
Before deprotection, the thietane ring should be
oxidized to thietane 1,1-dioxide by the action of excess
hydrogen peroxide in acetic acid (Scheme 4).
Scheme 4.
Scheme 6.
O
O
O
O
O
H2O2
RONa, ROH
Ht
S
Ht
S
Ht
S
Ht
H
+
RO
S
O
IIa, IIc–IIg
IIIa, IIIc–IIIg
IIIa, IIId–IIIi
Ia, Id–Ii
IVa, IVb
IV, R = Et (a), i-Pr (b).
Scheme 5.
Br
O
O
N
Thus the thietane ring can be readily introduced
into molecules of NH heterocycles, ensures their further
modification, and can be readily removed, i.e., it can
be used as protecting group.
N
N
S
NRR'
IIIh, IIIi
EXPERIMENTAL
O
S
O
The IR spectra were recorded on a Specord M-80
spectrometer from samples dispersed in mineral oil.
O
O
O
HNRR'
1
The H and 13C NMR spectra were measured on
Me
N
N
Ht
S
N
NRR'
a Bruker AM-300 instrument at 300 and 75 MHz, re-
spectively. The chemical shifts were determined rela-
tive to the corresponding sovent signals. The purity of
the isolated compounds was checked by thin-layer
chromatography on Silufol plates using hexane–etha-
nol (8:2) (I, III) and chloroform–ethanol (3:1) (II) as
eluents; spots were visualized by treatment with iodine
vapor.
IIIa, IIIc, IIId
O
N
Me
O
O
S
N
N
NRR'
Compound IIa was synthesized according to the
procedure described in [5], and compounds IIb–IId
were prepared as reported in [6].
R = H, R′ = PhCH2 (h), RR′N = piperidino (i).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 1 2009

THIETANE RING AS A NOVEL PROTECTING GROUP
137
3-Bromo-5-ethoxy-1-(thietan-3-yl)-1H-1,2,4-tri-
azole (IIe). Metallic sodium, 0.12 g (5 mmol), was
dissolved in 10 ml of anhydrous ethanol, a solution of
1.50 g (5 mmol) of compound IIa in 15 ml of anhy-
drous ethanol was added, and the mixture was heated
for 1 h under reflux (on a water bath) and filtered
while hot. The filtrate was cooled, and the precipitate
was filtered off, washed with water, and recrystallized
on heating, 1.70 g (50 mmol) of 37% hydrogen perox-
ide was added in one portion, and the mixture was
heated for 1 h under reflux. The mixture was cooled,
and the precipitate was filtered off, washed with water,
and dried.
3,5-Dibromo-1-(1,1-dioxo-λ6-thietan-3-yl)-1H-
1,2,4-triazole (IIIa). Yield 65%, mp 223–224°C (from
1
i-BuOH). H NMR spectrum (acetone-d6), δ, ppm:
1
from hexane. Yield 75%, mp 120–121°C. H NMR
4.66–4.98 m (4H, SCH)2), 5.55–5.75 m (1H, NCH).
Found, %: C 18.09; H 1.58; N 12.67. C5H5Br2N3O2S.
Calculated, %: C 18.14; H 1.52; N 12.70.
spectrum (CDCl3), δ, ppm: 1.45 t (3H, CH3, J =
7.1 Hz), 3.20–3.32 m (2H, SCH2), 3.95–4.08 m (2H,
SCH2), 5.39–5.54 m (1H, NCH), 4.47 q (2H, OCH2,
J = 7.1 Hz). Found, %: C 31.75; H 3.80; N 15.88.
C7H10BrN3OS. Calculated, %: C 31.83; H 3.82;
N 15.91.
3-Bromo-5-ethoxy-1-(1,1-dioxo-λ6-thietan-3-yl)-
1H-1,2,4-triazole (IIIe). Yield 85%, mp 166–167°C
1
(from i-PrOH). H NMR spectrum (CDCl3), δ, ppm:
1.46 t (3H, CH3, J = 7.0 Hz), 4.42–4.58 m (4H, SCH2,
OCH2), 4.67–4.83 m (2H, SCH2), 4.98–5.15 m
(1H, NCH). Found, %: C 28.29; H 3.45; N 14.15.
C7H10BrN3O3S. Calculated, %: C 28.39; H 3.40;
N 14.19.
3-Bromo-5-isopropoxy-1-(1,1-dioxo-λ6-thietan-
3-yl)-1H-1,2,4-triazole (IIIf). Yield 59%, mp 150–
151.5°C (from i-PrOH). Found, %: C 30.76; H 3.96;
N 14.10. C8H12BrN3O3S. Calculated, %: C 30.98;
H 3.90; N 13.55.
3-Bromo-5-isopropoxy-1-(thietan-3-yl)-1H-1,2,4-
triazole (IIf) was synthesized in a similar way using
isopropyl alcohol as solvent. The reaction mixture was
concentrated to 1/6 of the original volume, and the
precipitate was filtered off, washed with water, and
recrystallized from hexane. Yield 51%, mp 64–66°C.
Found, %: C 34.50; H 4.38; N 15.09. C8H12BrN3OS.
Calculated, %: C 34.54; H 4.35; N 15.11.
1-Alkyl-8-bromo-3-methyl-7-(thietan-3-yl)-1H-
purine-2,6(3H,7H)-diones IIc and IIg (general
procedure). Potassium hydroxide, 0.34 g (6 mmol),
was dissolved in 5 ml of water, 1.59 g (5 mmol) of
8-bromo-3-methyl-7-(thietan-3-yl)-1H-purine-
2,6(3H,7H)-dione (IIb), 50 ml of DMF, and 6 mmol of
methyl iodide or propyl iodide were added, and the
mixture was stirred for 4 h at room temperature. The
precipitate was filtered off, washed with water, and
recrystallized from ethanol.
8-Bromo-3-methyl-1-propyl-7-(1,1-dioxo-λ6-thi-
etan-3-yl)-1H-purine-2,6(3H,7H)-dione (IIIg). Yield
1
56%, mp 252°C (decom., from ethanol). H NMR
spectrum (CDCl3), δ, ppm: 0.95 t (3H, CH3, J =
7.42 Hz), 1.60–1.75 m (2H, CH2), 3.55 s (3H, 3-CH3),
3.96–4.05 m (2H, NCH2), 4.33–4.44 m and 5.19–
5.30 m (2H each, SCH2), 5.54–5.69 m (1H, NCH).
Found, %: C 36.94; H 3.90; N 14.38. C12H15BrN4O4S.
Calculated, %: C 36.84; H 3.86; N 14.32.
8-Bromo-1,3-dimethyl-7-(thietan-3-yl)-1H-
purine-2,6(3H,7H)-dione (IIc). Yield 66%, mp 220–
221°C. The product showed no depression of the melt-
ing point on mixing with an authentic sample prepared
according to the procedure described in [6].
5-Benzylamino-3-bromo-1-(1,1-dioxo-λ6-thietan-
3-yl)-1H-1,2,4-triazole (IIIh). Benzylamine, 4.20 g
(39 mmol), was added to a solution of 4.25 g
(13 mmol) of compound IIIa in 50 ml of butanol, and
the mixture was heated for 5 h under reflux. The mix-
ture was evaporated under reduced pressure, the oily
residue was ground with water, and the precipitate was
filtered off, washed with water, and recrystallized from
isopropyl alcohol. Yield 43%, mp 175–176°C. 1H NMR
spectrum (CDCl3), δ, ppm: 4.42 d (2H, NCH2, J =
5.6 Hz), 4.52–4.74 m (4H, SCH2), 4.70–4.90 m (1H,
NH), 5.18–5.34 m (1H, NCH), 7.26–7.40 m (5H,
C6H5), 7.58 t (1H, NH, J = 5.6 Hz). Found, %:
C 40.29; H 3.76; N 15.70. C12H13BrN4O2S. Calculated,
%: C 40.35; H 3.67; N 15.68.
8-Bromo-3-methyl-1-propyl-7-(thietan-3-yl)-1H-
purine-2,6(3H,7H)-dione (IIg). Yield 84%, mp 155–
156°C. 1H NMR spectrum (CDCl3), δ, ppm: 0.98 t (3H,
CH3, J = 7.0 Hz), 1.63–1.78 m (2H, CH2), 3.28–3.37 m
(2H, SCH2), 3.55 s (3H, 3-CH3), 4.00–4.07 m (2H,
NCH2), 4.36–4.46 m (2H, SCH2), 5.94–6.09 m
(1H, NCH). Found, %: C 40.20; H 4.25; N 15.55.
C12H15BrN4O2S. Calculated, %: C 40.12; H 4.21;
N 15.60.
N-(1,1-Dioxo-λ6-thietan-3-yl)azoles IIIa and IIIe–
IIIg (general procedure). Compound IIa or IIe–IIg,
5 mmol, was dissolved in 20 ml of glacial acetic acid
3-Bromo-1-(1,1-dioxo-λ6-thietan-3-yl)-5-piperi-
dino-1H-1,2,4-triazole (IIIi). Piperidine, 4.25 g
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 1 2009

KHALIULLIN, KLEN
138
(50 mmol), was added to a solution of 3.31 g
(10 mmol) of compound IIIa in 80 ml of butanol, and
the mixture was heated for 3 h under reflux. The mix-
ture was cooled, and the precipitate was filtered off,
washed with water, and recrystallized from isopropyl
N 19.34. C9H11BrN4O2. Calculated, %: C 37.65;
H 3.86; N 19.51.
5-Benzylamino-3-bromo-1H-1,2,4-triazole (Ih).
Yield 88% (a), mp 210.5–212°C (from i-PrOH).
1H NMR spectrum (DMSO-d6), δ, ppm: 4.32 d (2H,
NCH2, J = 6.4 Hz), 7.21–7.36 m (5H, C6H5), 7.43 t
(1H, NH, J = 5.7 Hz). Found, %: C 42.58; H 3.67;
N 22.31. C9H9BrN4. Calculated, %: C 42.71; H 3.58;
N 22.14.
1
alcohol. Yield 68%, mp 224–226°C. H NMR spec-
trum (CDCl3), δ, ppm: 1.50–1.90 m (6H, CH2), 2.95–
3.22 m (4H, NCH2), 4.40–4.68 m and 4.70–4.90 m (2H
each, SCH2), 4.92–5.15 m (1H, NCH). Found, %:
C 35.70; H 4.60; N 16.64. C10H15BrN4O2S. Calculated,
%: C 35.83; H 4.51, N 16.71.
3-Bromo-5-piperidino-1H-1,2,4-triazole (Ii).
1
Yield 84% (a), mp 216–218°C (from water). H NMR
NH-Heterocycles Ia and Id–Ii and 3-alkoxy-λ6-
thietane 1,1-dioxides IVa and IVb (general proce-
dure). A solution of 0.11 g (5 mmol) of metallic so-
dium and 5 mmol of the corresponding N-(dioxothi-
etanyl)-substituted heterocyclic compound in 20 ml of
ethanol (a) or isopropyl alcohol (b) was heated for
30 min under reflux. The mixture was evaporated
under reduced pressure, and the oily residue was
washed with 45 ml benzene. The undissolved material
was dissolved in water, the solution was acidified to
pH 3–4 with dilute acetic or hydrochloric acid, and the
precipitate was filtered off and washed with water to
isolate compound Ia or Id–Ii. The benzene solution
was evaporated, and the residue was dried and puri-
fied by reprecipitation from acetone with hexane. We
thus isolated compound IVa or IVb.
spectrum (CDCl3), δ, ppm: 1.55–2.00 m (6H, CH2),
3.10–3.70 m (4H, NCH2), 11.33 br.s (1H, NH). Found,
%: C 36.29; H 4.69; N 24.30. C7H11BrN4. Calculated,
%: C 36.38; H 4.80; N 24.24.
3-Ethoxy-λ6-thietane 1,1-dioxide (VIa). Yield
63%, mp 48–49°C. IR spectrum, ν, cm–1: 1143, 1320
(SO2). 1H NMR spectrum (CDCl3), δ, ppm: 1.20 t (3H,
CH3, J = 6.90 Hz), 3.45 q (2H, CH2O, J = 6.90 Hz),
4.00–4.20 m (2H, SCH2), 4.22–4.42 m (3H, SCH2,
OCH). Found, %: C 39.89; H 6.60; S 21.40. Calculat-
ed, %: C 39.95; H 6.66; S 21.30.
3-Isopropoxy-λ6-thietane 1,1-dioxide (VIb). Yield
94%, mp 50–51°C. IR spectrum, ν, cm–1: 1144, 1320
1
(SO2). H NMR spectrum (CDCl3), δ, ppm: 1.18 d
(6H, CH3, J = 6.13 Hz), 3.61 m (1H, CHO, J =
6.12 Hz), 4.04–4.15 m (2H, SCH2), 4.26–4.48 m (3H,
SCH2, OCH). Found, %: C 43.82; H 7.38; S 19.55.
Calculated, %: C 43.90; H 7.32; S 19.51.
3,5-Dibromo-1H-1,2,4-triazole (Ia). Yield 75%
(a), mp 210–212°C (from water). The product showed
no depression of the melting point on mixing with
an authentic sample prepared by bromination of
1,2,4-triazole.
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1
Yield 45% (a), mp 68–70°C (from ethanol). H NMR
spectrum (DMSO-d6), δ, ppm: 1.30 t (6H, CH3, J =
6.17 Hz), 4.90 m (1H, OCH, J = 6.17 Hz). Found, %:
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 1 2009