Synthesis of organoselenium sulfonamides as new potential cytokine inducers: 2,2'-Diselenobis(benzenesulfonamides) and 1,3,2- benzothiaselenazolone 1,1-dioxides

Article abstract of DOI:10.1002/(SICI)1099-0690(199901)1999:1<67::AID-EJOC67>3.0.CO;2-Q

A convenient method for the synthesis of 2,2'- diselenobis(benzenesulfonamides) 4 and 2-substituted 1,3,2- benzothiaselenazole 1,1-dioxides 2, has been elaborated. It is based on the conversion of 2-aminobenzenesulfonic acid into bis[2-(chlorosulfonyl)phe

Full text of DOI:10.1002/(SICI)1099-0690(199901)1999:1<67::AID-EJOC67>3.0.CO;2-Q

FULL PAPER
Synthesis of Organoselenium Sulfonamides as
New Potential Cytokine Inducers: 2,2 -Diselenobis(benzenesulfonamides)
and 1,3,2-Benzothiaselenazolone 1,1-Dioxides
Krystian Kloc[a] and Jacek Mlochowski*[a]
Keywords: 1,3,2-Benzothiaselenazole 1,1-dioxides / Cytokine inducers / Diselenobis(benzenesulfonamides) / Diselenides /
Sulfonamides
A convenient method for the synthesis of 2,2 -diseleno-
bis(benzenesulfonamides) 4 and 2-substituted 1,3,2-benzo-
thiaselenazole 1,1-dioxides 2, has been elaborated. It is
based on the conversion of 2-aminobenzenesulfonic acid into
bis[2-(chlorosulfonyl)phenyl] diselenide (6), and reaction
with ammonia or primary amines to give the sulfonamides 4.
Finally, cyclization of these sulfonamides by oxidation with
benzoyl peroxide or by treatment of their sodium or
potassium salt with elemental bromine produces 1,3,2-
thiaselenazole 1,1-dioxides 2.
Introduction
Benzisoselenazol-3(2H)-ones 1, in particular ebselen (1,
R
Ph), and the related 2,2 -diselenobis(benzenecarbox-
Scheme 1
amides) 3 [also named bis(2-carbamoylphenyl) diselenides]
are biomimetics of glutathione peroxidase. As such, they
act as biological response modifiers, mainly as anti-inflam-
matory agents, and are therefore objects of current interest
for organic chemists and medicinal biologists.[1][2] In our
previous works, some of these compounds were reported
as immunostimulants and virucides. They exhibited modest
activity as inducers of many different cytokines such as in-
terferons (mainly IFN- ), tumor necrosis factor (TNF- ),
and interleukines (IL-2, IL-4), and other factors in human
peripheral blood leukocyte cultures.[3 7] Moreover, some of
them exhibited activity as inhibitors of endothelial nitric
oxide synthase (ce NOS).[6,8,9]
Expecting that replacement of the carboxamide group in
compounds 1 and 3 by a sulfonamide group should result
in increase of their biological activity, we designed com-
pounds 2 and 4 as new potential immunostimulants and
virucides (Scheme 1). In this paper we report a general
method for the synthesis of 2,2 -diselenobis(benzenesulfon-
amides) 4 and their conversion into 1,3,2-benzothiaselen-
azole 1,1-dioxides 2 having a unique heterocyclic system with
the selenium, sulfur and nitrogen atoms in the same ring.
Although the synthesis of the first two representatives of
Results and Discussion
The key substrate for the synthesis of 2,2 -diselenobis-
(benzenesulfonamides) 4 was bis[2-(chlorosulfonyl)phenyl]
diselenide (6). It was obtained, in a total yield of 42% from
sodium 2-aminobenzenesulfonate (5) in a four-step syn-
thesis involving diazotization of 5 and reaction of the
diazonium salt with potassium selenocyanate. It resulted in
the formation of potassium 2-(cyanoseleno)benzenesul-
fonate which, when treated with aqueous potassium hydro-
xide, gave bis(2-sulfonylphenyl) diselenide which was then
converted into sulfonyl chloride 6 by heating with phos-
phorus pentachloride. The details of the synthetic pro-
cedure have been described in ref.[10]
Bis[2-(chlorosulfonyl)phenyl] diselenide (6) thus obtained
was treated with ammonia or primary aliphatic or aromatic
amines to give 2,2 -diselenobis(benzenesulfonamides) 4a
k
in 74 98% yield (Scheme 2). This procedure, although in-
volving five steps, seems to be more convenient and versatile
than the recently elaborated synthesis of 4 based on direct
lithiation and diselenenylation of phenylsulfonamides which
is limited only to sulfonamides 4 having an unsubstituted
phenyl or alkyl group[11] in the sulfamoyl moiety.
Seeking for a convenient method for the synthesis of
1,3,2-benzothiaselenazole 1,1-dioxides 2, we tested different
reactions leading to compound 2d, presented in Scheme 3.
Although the simplest way seemed to be direct cyclocon-
densation of a primary amine with 2-(chloroseleno)ben-
zenesulfonyl chloride, the reaction could not be carried out
because of the instability of the reagent.[10] A more stable
reagent was 2-(bromoseleno)benzenesulfonyl chloride (7),
compounds 2 [R
CH3, C(CH3)3], obtained earlier in our
laboratory, have already been reported[10,11] the problem of
a general synthesis of different 2-substituted 1,3,2-benziso-
thiaselenazole 1,1-dioxides has not yet been resolved.
[a]
Institute of Organic Chemistry, Biochemistry and Biotechno-
logy, Wroclaw University of Technology,
Wyb. Wyspianskiego 27, PL-50 370, Wroclaw, Poland
Fax: (internat.) 48-71/3284064
E-mail: Mlochowski@kchf.ch.pwr.wroc.pl
Eur. J. Org. Chem. 1999, 67 71
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434 193X/99/0101 0067 $ 17.50 .50/0
67

K. Kloc, J. Mlochowski
FULL PAPER
Scheme 2. (i) 1. NaNO2, H2SO4, 10°C; 2. KSeCN, H2O, 0°C;
3. KOH, H2O; 4. PCl5, 150°C.
10° to 20°C
(ii) RNH2, CH2Cl2 or pyridine,
obtained from sulfonyl chloride by treatment with elemen-
tal bromine. Compound 7 was treated with tert-butylamine
to give 2d (Method A). The second method which led to 2d
(Method B) was based on the conversion of 2,2 -diseleno-
bis(N-tert-butylbenzenesulfonamide) (4d) into 2-(bromose-
leno)benzenesulfonamide (8d) followed by elimination of
hydrogen bromide using triethylamine as a base. Treatment
of other (bromoseleno)benzenesulfonamides 8a, b, j, k with
triethylamine, however, gave only the starting diselenides
4a, b, j, k. Another approach (Method C) was based on the
conversion of 4d into sodium salt 9 and its direct cyclization
(without isolation of 9) into 2d using elemental bromine.
Although Methods A C led to the desired product 2d,
its yield did not exceed 21%, and the product was ac-
companied by substantial amounts (42 62%) of starting
diselenide 4d. More efficient was a two-step reaction
(Method D) which involved conversion of 4d into potas-
sium salt 10 and subsequent ring closure with elemental
bromine. In this way, the corresponding products 2d and
2i were obtained in 49% and 27% yields from 4d and 4i,
respectively. Unfortunately, the scope of this method was
limited to these two examples, and from other salts, ob-
tained from 4a c and 4d h, only the starting substrates 4
were recovered.
Scheme 3. (i) Br2, CCl4, 10 to 20°C. (ii) H2NC(CH3)3, CH2Cl2,
10°C.
(iii) (C2H5)3N, CCl4, 10°C.
(iv) NaH, CH2Cl2,
20°C. (v) Br2, CH2Cl2, 10 to 20°C. (vi) tBuOK, tBuOH, re-
flux
Scheme 4
Experimental Section
General: Melting points: Digital Melting Point Apparatus Electro-
thermal IA 9100.
IR (KBr pellets): Perkin-Elmer 2000 FT.
1H NMR: Bruker 300-MHz spectrometer.
The recently reported generation of the amidyl radical
from 2-(triphenylstannylseleno)benzamides with benzoyl
peroxide[12] prompted us to carry out the oxidative cycliza-
tion of 2,2 -diselenobis(benzenesulfonamides) 4 to 1,3,2-
benzisoselenazole 1,1-dioxides 2 using the same reagent as
an oxidant (Scheme 4). The desired products 2b h, among
them 2f which is a close analogue of ebselen, were obtained
in 13 49% yield. They were accompanied by the di-
All starting materials
were purchased from Aldrich Chem. Co. and Fluka.
Synthesis of 2,2 -Diselenobis(benzenesulfonamides) 4a k.
Gen-
eral Procedure: A solution of amine (50 mmol) in dry dichloro-
methane (25 mL) was added dropwise over a period of 1 h to a
stirred and cooled (ice/salt bath) solution of sulfonyl chloride 6
(2.55 g, 5 mmol) (obtained according to the procedure reported
in ref.[10]) in dry dichloromethane (50 mL). The gaseous substrate
selenides 4b h which could be recovered in 24 54% yields. (ammonia, methylamine) was passed through the reaction mixture
until all of 6 was exhausted (ca. 15 min). After 3 h, during which
the mixture was allowed to warm to room temperature, the solvent
and excess of amine were removed in vacuo. From the residue,
amine hydrochloride was washed off by stirring with water over a
period of 6 h and the product 4a d was filtered off and recrys-
tallized from methanol. When a low-volatility amine (cyclohexyl-
amine, arylamine) (11 mmol) was used as a substrate, it was dis-
solved in dry pyridine (25 mL), and to this stirred and cooled (ice
bath) solution, sulfonyl chloride 6 (2.55 g, 5 mmol) was added por-
tionwise over a period of 30 min. After 3 h (4e j) or 20 h (4k),
during which the reaction mixture was allowed to warm to room
The oxidative cyclization of 4 presented seems to be the
most general method for the synthesis of 2, although it is
limited by the solubility of the substrate in benzene and the
susceptibility towards side-oxidative transformations. Thus,
insoluble 4h gave product 2h in 13% yield only and for 4a,
j, k no formation of 2a, j, k was observed. The reaction of
4i was more complex, most probably because of the sen-
sitivity of its aromatic moiety towards oxidation, and only
a tar-like mixture of several unidentified products was ob-
tained.
68
Eur. J. Org. Chem. 1999, 67 71

Organoselenium Sulfonamides as New Potential Cytokine Inducers
FULL PAPER
temperature, the pyridine was evaporated in vacuo. To the residue,
water (100 mL) (for 4k) or 5% hydrochloric acid (for 4e i) was
added. It was then stirred for 6 h, the product filtered off, dried in
air, dissolved in chloroform (4e, f, g, i), acetone (4h) or methanol
(4j) and filtered through silica gel. The solvent was evaporated from
the filtrate in vacuo and the residue was recrystallized from chloro-
form (4h), chloroform/hexane (1:1) (4e, f, g, i) or water/acetone
(5:1) (4i) to give a pure product which was dried in air (4e i) or
at a temperature of 120°C (4j). For isolation of 4k, the residue after
pyridine evaporation was suspended in satd. aq. sodium hydrogen
carbonate (80 mL) and stirred until carbon dioxide evolved (ca. 5
h). The product was filtered off, washed with water, methanol and
recrystallized from DMSO/methanol.
ArH); 7.64 (dd, 2 H, J
8.7 Hz, ArH); 7.94 (dd, 2 H, J
2 H, NH); 12.77 (s, 2 H, COOH).
(SO2), 1683 (CO), 2540 3060 (OH), 3244 (NH).
C26H20N2O8S2Se2 (710.48): calcd. C 43.95, H 2.84, N 3.94, S 9.02;
found C 43.71, H 3.11, N 4.10, S 8.70.
7.9 and 0.6 Hz, ArH); 7.83 (d, 4 H, J
7.8 and 1.2 Hz, ArH); 11.26 (s,
IR: ˜
1158 cm 1, 1337
2,2 -Diselenobis[N-(2-pyridyl)benzenesulfonamide] (4k): Yellow
powder 2.68 g (86%), m.p. 280 281°C.
TMS): 6.84 (t, 2 H, J 6.5 Hz, PyH); 7.19 (d, 2 H, J
4.5 Hz, ArH); 7.34 (t, 2 H, J
1H NMR (DMSO,
8.9
7.4,
Hz, PyH); 7.25 (t, 2 H, J
ArH); 7.62 (d, 2 H, J
7.8 Hz, ArH); 7.78 7.83 (m, 2 H, PyH);
7.91 7.96 (m, 4 H, ArH and PyH); 12.62 (s, 1 H, NH). IR: ˜
1142 cm 1, 1383 (SO2), 3221 (NH).
C22H18N4O4S2Se2 (624.43):
2,2 -Diselenobis(benzenesulfonamide) (4a): Pale yellow powder.
calcd. C 42.31, H 2.90, N 8.97, S 10.27; found C 42.02, H 3.20, N
8.52, S 10.61.
Yield 2.12 g (90%), m.p. 253 255°C (decomp.).
(DMSO, TMS): 7.42 7.50 (m, 4 H, ArH); 7.75 (s, 4 H, NH2);
7.78 7.84 (m, 2 H, ArH); 7.86 7.91 (m, 2 H, ArH). IR: ˜
1153 cm 1, 1328 (SO2), 3250, 3363 (NH2).
C12H12N2O4S2Se2
(470.28): calcd. C 30.65, H 2.57, N 5.96, S 13.63; found C 30.82,
H 2.85, N 5.78, S 13.40.
1H NMR
2-(Bromoseleno)benzenesulfonyl Chloride (7): A solution of bromine
(1.34 g, 8.4 mmol) in dry carbon tetrachloride (30 mL) was added
dropwise to a suspension of chloride 6 (4.07 g, 8 mmol) in carbon
tetrachloride (30 mL). The mixture was vigorously stirred and
cooled on an ice/salt bath for 30 min. After 3 h, during which the
mixture was allowed to warm to room temperature, the solvent was
evaporated in vacuo. The residue recrystallized from hexane giving
2,2 -Diselenobis(N-methylbenzenesulfonamide) (4b): Yellow prisms.
Yield 2.78 g (74%), m.p. 185 187°C (ref.[10] 185 187°C).
compound 7 as red prisms (5.0 g, 93%), m.p. 40 41°C.
NMR (CDCl3, TMS): 7.51 (dt, 1 H, J 7.6 and 1.0 Hz, ArH);
1H
2,2 -Diselenobis(N-propylbenzenesulfonamide) (4c): Yellow prisms.
Yield 2.56 g (92%), m.p. 130 132°C (ref.[11] 125 128°C).
7.70 (dt, 1 H, J
7.8 and 1.4 Hz, ArH); 8.03 (dd, 1 H, J
7.6
2,2 -Diselenobis(N-tert-butylbenzenesulfonamide)
(4d):
Yellow
and 1.4 Hz, ArH); 8.05 (dd, 1 H, J
˜
8.1 and 1.0 Hz, ArH). IR:
prisms. Yield 2.68 g (92%), m.p. 208 209°C (ref.[11] 207 209°C).
1172 cm 1, 1364 (SO2). Elemental analyses gave irreproduc-
ible results.
2,2 -Diselenobis(N-cyclohexylbenzenesulfonamide) (4e): Yellow
prisms. Yield 2.70 g (85%), m.p. 210 212°C (ref.[11] 210 212°C).
Synthesis of the 2-(Bromoseleno)benzenesulfonamides 8a, b, d, j, k.
General Procedure: To a stirred suspension of 4 (1.0 mmol) in
dry carbon tetrachloride (25 mL) cooled with an ice/salt bath, a
solution of bromine in the same solvent (10 mL) was added drop-
wise during 30 min. During the following 3 h (8b,d) or 24 h (8a, j,
k) the mixture was allowed to warm to room temperature. For 8b,
d the solvent was evaporated in vacuo from the water bath
(30 35°C) and the crude product was recrystallized from hexane.
The products 8a, j, k were filtered off from the reaction mixture,
washed with carbon tetrachloride and dried in air. The compounds
8a, b, d, j, k were identified by IR and 1H-NMR spectroscopy.
Elemental analyses gave irreproducible results.
2,2 -Diselenobis(N-phenylbenzenesulfonamide) (4f): Yellow needles.
Yield 2.55 g (82%), m.p. 155 157°C (ref.[11] 154 155°C).
2,2 -Diselenobis[N-(4-methylphenyl)benzenesulfonamide] (4g): Yel-
low needles 3.19 g (98%), m.p. 175 177°C.
1H NMR (CDCl3,
2.25 (s, 6 H, CH3); 6.86 (d, 4 H, J 8.4 Hz, ArH);
TMS):
6.97 (s, 2 H, NH); 7.01 (d, 4 H, J
47.4 Hz, ArH); 7.24 (dt, 2 H,
J
7.5 and 1.2 Hz, ArH); 7.31 (dt, 2 H, J 7.5 and 1.7 Hz, ArH);
7.76 (dd, 2 H, J 7.7 and 1.6 Hz, ArH); 7.82 (dd, 2 H, J 7.7
and 1.7 Hz, ArH). IR: ˜
1153 cm 1, 1331 (SO2), 3298 (NH).
C26H24N2O4S2Se2 (650.51): calcd. C 48.00, H 3.72, N 4.39, S
9.86; found C 47.8, H 3.89, N 4.60, S 9.70.
2-(Bromoseleno)benzenesulfonamide (8a): Orange-red powder. Yield
2,2 -Diselenobis[N-(4-chlorophenyl)benzenesulfonamide] (4h): Yel-
low needles 3.18 g (92%), m.p. 184 186°C.
0.59 g (94%), m.p. 188 190°C (decomp.).
TMS): 7.44 (t, 1 H, J 6.6 Hz, ArH); 7.59 (t, 1 H, J
8.9 Hz, ArH); 8.09 (d, 1 H, J
1H NMR (DMSO,
1H NMR (CDCl3,
7.6
7.9
TMS):
(d, 4 H, J
(m, 4 H, ArH).
6.93 (d, 4 H, J
6.7 Hz, ArH); 7.30 7.38 (m, 4 H, ArH); 7.78 7.82
IR: ˜
1154 cm 1, 1328 (SO2), 3294 (NH).
6.7 Hz, ArH); 7.08 (s, 2 H, NH); 7.17
Hz, ArH); 7.69 (d, 1 H, J
Hz, ArH); 9.50 (br. s, 2 H, NH2).
(SO2), 3242, 3353 (NH2).
IR: ˜
1165 cm 1, 1329
C24H18Cl2N2O4S2Se2 (691.35): calcd. C 41.69, H 2.62, Cl 10.27, N
4.05, S 9.27; found C 41.94, H 2.69, Cl 10.50, N 3.86, S 9.0.
2-(Bromoseleno)-N-methylbenzenesulfonamide (8b): Orange-red
needles. Yield 0.62 g (94%), m.p. 91 93°C (decomp.). 1H NMR
2,2 -Diselenobis[N-(4-methoxyphenyl)benzenesulfonamide] (4i): Yel-
low prisms 3.17 g (93%), m.p. 183 185°C.
1H NMR (CDCl3,
3.73 (s, 6 H, CH3); 6.71 (d, 4 H, J 9.0 Hz, ArH);
(CDCl3, TMS):
H, NH); 7.43 (t, 1 H, J
ArH); 7.59 (td, 1 H, J
2.69 (d, 3 H, J
7.6 Hz, ArH); 7.59 (td, 1 H, J
7.7 and 1.4 Hz, ArH); 7.81 (dd, 1 H, J
5.4 Hz, CH3); 4.87 (br. s, 1
7.6 Hz
TMS):
6.90 (d, 4 H, J
9.0 Hz, ArH); 6.93 (s, 2 H, NH); 7.24 (dt, 2 H,
7.8 and 1.3 Hz, ArH); 8.00 (d, 1 H, J
1154 cm 1, 1320 (SO2), 3288 (NH).
8.0 Hz, ArH). IR: ˜
J
7.5 and 1.1 Hz, ArH); 7.35 (dt, 2 H, J 7.6 and 1.5 Hz, ArH);
7.70 (dd, 2 H, J 7.7 and 1.5 Hz, ArH); 7.84 (dd, 2 H, J 7.9
and 1.7 Hz, ArH). IR: ˜
1154 cm 1, 1332 (SO2), 3290 (NH).
2-(Bromoseleno)-N-tert-butylbenzenesulfonamide (8d): Reddish-
brown needles. Yield 0.68 g (92%), m.p. 90 91°C (decomp.). 1H
C26H24N2O6S2Se2 (682.51): calcd. C 45.75, H 3.54, N 4.10, S
9.39; found C 46.00, H 3.64, N 4.36, S 9.32.
NMR (CDCl3, TMS):
7.6 and 1.1 Hz, ArH); 7.54 (dt, 1 H, J
and 1.5 Hz, ArH); 7.85 (dd, 1 H, J 7.7 and 1.5 Hz, ArH); 7.97
(dd, 1 H, J 8.0 and 1.0 Hz, ArH). IR: ˜
1150 cm 1, 1290
(SO2), 2972 (CH), 3297 (NH).
1.25 (s, 9 H, CH3); 5.00 (s, 1 H, NH);
2,2 -Diselenobis[N-(4-carboxyphenyl)benzenesulfonamide] (4j): Pale 7.40 (dt, 1 H, J
yellow powder 3.33 g (94%), m.p. 196 199°C.
1H NMR
(DMSO, TMS): 7.22 (d, 4 H, J 8.7 Hz, ArH); 7.31 (dt, 2
H, J 7.7 and 14.3 Hz, ArH); 7.41 (dt, 2 H, J 7.5 and 1.0,
7.7
Eur. J. Org. Chem. 1999, 67 71
69

K. Kloc, J. Mlochowski
FULL PAPER
2-(Bromoseleno)-N-(4-carboxyphenyl)benzenesulfonamide (8j): Red-
dish-brown needles. Yield 0.83 g (96%), m.p. 203 204°C (de-
70°C for 24 h. After the reaction had finished, the benzene was
evaporated in vacuo and the residue was separated by silica gel
chromatography (dichloromethane) to give 2, which was recrys-
tallized from carbon tetrachloride (2b d), methanol (2g, h), ben-
comp.). 1H NMR (DMSO, TMS):
7.27 (d, 2 H, J
8.7 Hz,
ArH); 7.50 (dt, 1 H, J
7.5 and 0.8 Hz, ArH); 7.64 (dt, 1 H, J
7.7 and 1.2 Hz, ArH); 7.73 (dd, 1 H, J
7.7 and 1.3 Hz, ArH); zene (2f) or cyclohexane/benzene (1:1) (2e). The next eluted frac-
7.9 Hz, ArH); 9.99 tion was compound 4 (4b, 26%; 4c, 33%; 4d, 32%; 4e, 42%; 4f, 24%;
1157 cm 1, 1328 (SO2), 1680 4g, 36%; 4h, 54%).
7.87 (d, J
6.8 Hz, ArH); 8.32 (d, 1 H, J
IR: ˜
(br. s, 2 H, NH, COOH).
(CO), 2548 3010 (OH), 3267 (NH).
2-Methyl-1,3,2-benzothiaselenazole 1,1-Dioxide (2b): White needles.
Yield 0.262 g (54%), m.p. 98 100°C (ref.[10] 98 100°C).
2-(Bromoseleno)-N-(2-pyridyl)benzenesulfonamide (8k): Orange-red
powder. Yield 0.69 g (88%), m.p. 213 214 (decomp.). 1H NMR
2-Propyl-1,3,2-benzothiaselenazole 1,1-Dioxide (2c): Colourless
prisms. Yield 0.25 g (46%), m.p. 84 86°C.
TMS): 0.96 (t, 3 H, J 7.3 Hz, CH3); 1.67 (sext, 2 H, J
7.3 Hz, CH2CH3); 3.30 (t, 2 H, J 7.3 Hz, NCH2), 7.44 (dt, 1 H,
7.4 and 1 Hz, ArH); 7.49 (d, 1 H, J 7.6 Hz, ArH); 7.58 (dt,
7.6 and 1.2 Hz, ArH); 7.76 (d, 1 H, J 7.5 Hz, ArH).
1H NMR (CDCl3,
(CDCl3/DMSO, TMS):
(m, 1 H, ArH); 7.46 7.52 (m, 2 H, ArH, PyH); 7.76 7.91 (m, 3 H,
ArH, PyH); 13.1 (br. s, 1 H, NH); 8.05 (dd, 1 H, J 8.1 and 1.1
Hz, ArH). IR: ˜
1152 cm 1, 1344 (SO2), 3224 (NH).
6.84 6.89 (m, 1 H, PyH); 7.36 7.41
J
1 H, J
Synthesis of 2-tert-Butyl-1,3,2-benzothiaselenazole 1,1-Dioxide (2d).
Method A: A solution of compound 7 (0.502 g, 1.5 mmol) in
dry dichloromethane (10 mL) was added dropwise over 1 h to a
stirred and cooled (ice/salt bath) solution of tert-butylamine (0.33
g, 4.5 mmol) in dry dichloromethane (10 mL). After additional 30
min, the precipitated solid was filtered off, the solvent was evapo-
rated from the filtrate in vacuo, and from the residue 2d was sepa-
rated by the silica gel chromatography (dichloromethane), and
recrystallized from carbon tetrachloride. Yield 0.069 g (16%). The
next eluted fraction was 4c (0.182 g, 42%). Method B: A solution
of compound 8d (0.722 g, 2.0 mmol) in dry carbon tetrachloride
(20 mL) was added dropwise to a solution of triethylamine (0.223
g, 2.2 mmol) in the same solvent (20 mL), cooled with an ice/salt
bath, over a period of 30 min. During the following 3 h, the mixture
was allowed to warm to room temperature. From the reaction mix-
ture, worked up as outlined in Method A, 2d (0.083 g, 14%) and
IR: ˜ 1600 cm 1, 1320 (SO2). C9H11NO2SSe (276.21): calcd. C
39.19, H 4.01, N 5.07, S 11.61; found C 39.40, H 4.21, N 4.80,
S 11.45.
2-tert-Butyl-1,3,2-benzothiaselenazole 1,1-Dioxide (2d): Colourless
needles. Yield 0.35
g
(61%), m.p. 112.5 115°C (ref.[11]
113 115°C).
2-Cyclohexyl-1,3,2-benzothiaselenazole 1,1-Dioxide (2e): Colourless
flakes. Yield 0.23 g (36%), m.p. 205 206°C (decomp.). 1H NMR
(CDCl3, TMS):
CH2); 3.73 3.82 (m, 1 H, CH); 7.38 7.43 (m, 1 H, ArH); 7.48 (d,
1 H, J 6.9 Hz, ArH); 7.51 7.57 (m, 1 H, ArH); 7.71 (d, 1 H,
7.4 Hz, ArH). IR: ˜
1170 cm 1, 1329 (SO2), 2853, 2926
C12H15NO2SSe (316.27): calcd. C 45.57, H 4.78, N 4.43,
1.23 1.34 (m, 4 H, CH2); 1.61 1.72 (m, 6 H,
J
(CH).
S 10.14; found C 45.71, H 4.58, N 4.70, S 10.07.
2-Phenyl-1,3,2-benzothiaselenazole 1,1-Dioxide (2f): Colourless
4d (0.249 g, 50%) were isolated.
Method C: A solution of com-
needles. Yield 0.19 g (31%), m.p. 192 194°C (decomp.).
NMR (CDCl3, TMS): 7.18 7.30 (m, 5 H, ArH); 7.48 (t, 1 H,
7.2 Hz ArH); 7.60 (d, 1 H, J 7.2 Hz, ArH); 7.64 (t, 1 H,
7.4 Hz, ArH), 7.78 (d, 1 H, J 7.8 Hz, ArH). IR: ˜ 1170
C12H9NO2SSe (310.22): calcd. C 46.46, H
1H
pound 4d (1.456 g, 2.5 mmol) in dry dichloromethane (25 mL)
was added at room temperature to a suspension of oil-free sodium
hydride (0.132 g, 5.5 mmol) in anhydrous dichloromethane (25
mL), and the reaction was continued for 5 d, until the evolution of
hydrogen had ceased. To this mixture, cooled with an ice/salt bath,
a solution of bromine (0.440 g, 2.75 mmol) in dichloromethane (25
mL) was added dropwise. During the following 18 h the mixture
was allowed to warm to room temperature and then it was worked
up as in Method A to give 2d (0.307 g, 21%) and 4d (0.901 g, 62%).
Method D: A 100-mL round-bottom flask containing a solution
of potassium tert-butoxide (0.294 g, 2.62 mmol) in dry tert-butyl
alcohol (50 mL), was fitted with a pressure-equalising dropping
funnel, containing 4d (0.872 g, 1.25 mmol). The funnel was stop-
pered with a moisture-protected condenser and the solution in the
flask was magnetically stirred and refluxed until all 4d had dis-
solved (ca. 2 h). Heating was then continued for 1 h. After the
reaction had finished, tert-butyl alcohol was decanted and the rest
of it was removed in vacuo to give 10 (0.763 g, 1.16 mmol, 93%).
The product was suspended in dry carbon tetrachloride (60 mL)
and to this suspension, stirred and cooled on an ice/salt bath, a
solution of bromine (0.203 g, 1.27 mmol) in dry carbon tetra-
chloride (20 mL) was added dropwise during 1.5 h. During the
following 18 h the mixture was allowed to warm to room tempera-
ture. Then it was heated and potassium bromide was filtered off
and washed with hot carbon tetrachloride. The solvent was re-
moved from the filtrate under reduced pressure to yield pure 2d
(0.387 g, 53%).
J
J
cm 1, 1339 (SO2).
2.92, N 4.52, S 10.33; found C 46.70, H 3.19, N 4.30, S 10.50.
2-(4-Methylphenyl)-1,3,2-benzothiaselenazole 1,1-Dioxide (2g): Pale
yellow needles. Yield 0.17 g (27%), m.p. 194 195°C (decomp.).
1H NMR (CDCl3, TMS):
2.31 (s, 3 H, CH3), 7.06 7.12 (m, 4
H, ArH); 7.44 7.49 (m, 1 H, ArH), 7.58 7.67 (m, 2 H, ArH);
7.75 7.78 (m, 1 H, ArH). IR: ˜
1171 cm 1, 1346 (SO2).
C13H11NO2SSe (324.25): calcd. C 48.15, H 3.42, N 4.32, S 9.89;
found C 48.43, H 3.57, N 4.53, S 9.80.
2-(4-Chlorophenyl)-1,3,2-benzothiaselenazole 1,1-Dioxide (2h): Pale
yellow prisms. Yield 0.09 g (13%), m.p. 159 160°C (decomp.).
1H NMR (CDCl3, TMS):
7.15 (d, 2 H, J 8.9 Hz, ArH); 7.25
8.9 Hz, ArH); 7.49 (dt, 1 H, J 7.3 and 1.4 Hz,
(d, 2 H, J
ArH); 7.61 (dd, 1 H, J
7.8 and 1.5 Hz, ArH); 7.67 (dt, 1 H, J
7.5 and 1.2 Hz, ArH); 7.76 (dd, 1 H, J
8.2 and 0.8 Hz, ArH).
IR: ˜ 1160 cm 1, 1334 (SO2). C12H8ClNO2SSe (344.67): calcd.
41.81, H 2.34, N 4.06, S 9.30, Cl 10.28; found C 41.62, H 2.29, N
4.16, S 9.49, Cl 10.14.
2-(4-Methoxyphenyl)-1,3,2-benzothiaselenazole 1,1-Dioxide (2i),
Obtained by Method D: Yellow plates. Yield 0.23 g (27%), m.p.
152 153°C (decomp.). 1H NMR (CDCl3, TMS):
3.77 (s, 3
8.9 Hz, ArH); 7.13 (d, 2 H, J 8.9
H, OCH3); 6.78 (d, 2 H, J
Hz, ArH); 7.47 (t, 1 H, J
Hz, ArH); 7.65 (t, 1 H, J
7.4 Hz, ArH); 7.59 (d, 1 H, J
7.4 Hz, ArH); 7.78 (d, 1 H, J
1176 cm 1, 1342 (SO2).
7.5
7.7
General Procedure for the Synthesis of 1,3,2-Benzothiaselenazole
1,1-Dioxides 2b h by Oxidative Cyclization of 4b h: A mixture of
the appropriate compound 4 (1.0 mmol), benzoyl peroxide (0.266
g, 1.1 mmol) and dry benzene (30 mL) was stirred and heated to
Hz, ArH).
IR: ˜
C13H11NO3SSe
(340.25): calcd. C 45.89, H 3.26, N 4.12, S 9.42; found C 45.60, H
3.24, N 4.06, S 9.00.
70
Eur. J. Org. Chem. 1999, 67 71

Organoselenium Sulfonamides as New Potential Cytokine Inducers
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