Novel analogues of ebselen - Preparation of 2-alkylthieno[2,3-d]isoselenazol-3(2H)-ones by peroxide-mediated ring-closure of 3,3′-diselenobis(N-alkylthiophencarboxamides)

Article abstract of DOI:10.1071/CH99127

Studies toward the preparation of novel thiophen analogues of the anti-inflammatory compound Ebselen are presented. We report that treatment of 3,3′-diselenobis(N-alkylthiophen-2-carboxamides) (13; R = Me, Prⁱ, Bu^t, Ph) with benzoyl peroxide in benzene under reflux affords the corresponding 2-alkylthieno[2,3-d]isoselenazol-3(2H)-ones (7) in 10-73% yield, except for the phenyl derivative (13; R = Ph) which proved too insoluble to react. Irradiation of the PTOC imidate esters of 2-benzylseleno-N-butylthiophen-3-carboxamide (9) and 3-benzylseIeno-N-butylthiophen-2-carboxamide (12) provides none of the expected Ebselen analogues. This failure to ring-close is discussed in terms of conformational rigidity in amidyl radicals (22) and (23). CSIRO 2000.

Full text of DOI:10.1071/CH99127

C S I R O P U B L I S H I N G
Australian Journal
of Chemistry
Volume 53, 2000
©
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Aust. J. Chem., 2000, 53, 277–283
Novel Analogues of Ebselen—Preparation of
-Alkylthieno[2,3-d]isoselenazol-3(2H)-ones
by Peroxide-Mediated Ring-Closure of
,3Ј-Diselenobis(N-alkylthiophencarboxamides)*
2
3
A
A,B
A
Melissa J. Laws, Carl H. Schiesser, Jonathan M. White and
Shi-Long Zheng
A,C
A
School of Chemistry, The University of Melbourne, Vic. 3010.
Author to whom correspondence should be addressed.
Current address: School of Pharmacy, West China University of Medical Sciences,
B
C
Chengdu, Sichuan 610041, China.
Studies toward the preparation of novel thiophen analogues of the anti-inflammatory compound Ebselen are pre-
i
t
sented. We report that treatment of 3,3Ј-diselenobis(N-alkylthiophen-2-carboxamides) (13; R = Me, Pr , Bu , Ph)
with benzoyl peroxide in benzene under reflux affords the corresponding 2-alkylthieno[2,3-d]isoselenazol-3(2H)-
ones (7) in 10–73% yield, except for the phenyl derivative (13; R = Ph) which proved too insoluble to react.
Irradiation of the PTOC imidate esters of 2-benzylseleno-N-butylthiophen-3-carboxamide (9) and 3-benzylseleno-N-
butylthiophen-2-carboxamide (12) provides none of the expected Ebselen analogues. This failure to ring-close is
discussed in terms of conformational rigidity in amidyl radicals (22) and (23).
Keywords. Ab initio molecular orbital calculations; diselenide; selenium; synthesis; thiophen; X-ray crystal struc-
ture.
6
Introduction
closure chemistry. While the former chemistry could be
applied to the preparation of Ebselen analogues, it failed to
provide Ebselen itself mainly because of our inability to
prepare a suitable radical precursor when the amide (2) was
Glutathione peroxidase is a mammalian selenoenzyme
that catalyses the reduction of a wide variety of hydroperox-
ides which are known to generate highly reactive oxygen
radicals that destroy key biological molecules and cause
7
phenyl-substituted. For example, treatment of (2) with
1
damage to cell membranes. The activity of glutathione per-
trimethylsilyl triflate followed by phosgene, as described by
Newcomb and Esker, afforded the rare selenazine-2,4(3H)-
dione ring system (4) which itself proved to have interesting
biological properties. † Reactions of suitable diselenides (5)
8
oxidase is principally due to the redox chemistry surround-
ing the selenocystine residue found in the active site of the
1
9
enzyme.
Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) (1;
with benzoyl peroxide, however, afforded the required com-
pounds in good to excellent yields in what we believe to be
non-radical processes (Scheme 1).
R = Ph) and some of its derivatives mimic the action of glu-
1
6
tathione peroxidsase. The sulfur analogue is completely
inactive, an observation which highlights the importance of
As part of ongoing studies directed toward the develop-
ment of novel chalcogen-containing antioxidants, we
2
10
selenium in this redox chemistry. Ebselen has also been
3
shown to be a nitric oxide synthase inhibitor, to induce
began to explore methods for the construction of thiophen-
modified analogues (6) and (7) of Ebselen. These com-
pounds may be expected to provide superior solubility prop-
erties to (1) while maintaining a diverse range of interesting
biological properties and as such are appropriate synthetic
targets. Interestingly, while these compounds (6) and (7) are
cytokines such as interferons, tumour necrosis factor, inter-
leukin-2 and gratunocytemacrophate colony stimulating
4
factor. These properties combined with Ebselen’s low toxi-
city have lead to interest in its therapeutic potential for a
5
number of diseases. Ebselen has been the subject of clinical
5
11
trials as an anti-inflammatory and antioxidant.
described in the original patents, it would appear that these
1
2
Recently, we reported that Ebselen and other benzo ana-
logues (1) could be prepared either by radical or ionic ring-
structures have never been prepared. In this paper we report
that 2-alkylthieno[2,3-d]isoselenazol-3(2H)-ones (7) are
*
†
Dedicated to Professor Don Cameron in grateful recognition of his many contributions to chemistry and the University of Melbourne.
Preliminary pharmacological testing revealed that benzoselenazine-2,4(3H)-diones (3) demonstrated inhibition of purinergic transmission at the
neuromuscular junction in rat vas deferens, and inhibition of endothelium-dependent relaxation in vascular tissue.
Manuscript received 29 September 1999 © CSIRO 2000 10.1071/CH99127
0004-9425/00/040277

2
78
M. J. Laws et al.
acid (11), as an inseparable mixture. Reaction of this mixture
with oxalyl chloride followed by butylamine resulted in the
expected mixture of isomeric amides. Separation by flash
chromatography provided, as the band of higher R , the
F
amide (12) in 29% yield. 5-Benzylseleno-N-butylthiophen-
carboxamide was isolated in 6% yield as the product of
lower R .
F
readily available by treatment of 3,3Ј-diselenobis(N-alkyl-
thiophencarboxamides) (13) with benzoyl peroxide.
Results and Discussion
Attempted Ring-Closure Using Imidate Esters Derived from
Thiophencarboxamides
With the amides (9) and (12) in hand, we next turned our
attention to the preparation of suitable PTOC imidate ester
radical precursors.† Following the procedure of Newcomb
and Esker, amide (9) was treated with 20% phosgene in
toluene. The intermediate iminyl chloride was not isolated,
but immediately reacted with the sodium salt of N-hydrox-
ypyridine-2-thione to afford the PTOC imidate ester (14) as a
thick green oil which was used without further purification
Given our success in preparing analogues of Ebselen
through the photochemical decomposition of PTOC imidate
esters (3)* derived from N-alkyl-2-benzylselenobenzamides
(2), we began this work by exploring the feasibility of effect-
ing similar transformations with thiophencarboxamides (9)
and (12). Amide (9) was prepared from the acid chloride (8)
1
3,14
7
(Scheme 3).
‡
following our previously reported procedure (Scheme 2). 2-
To our surprise, when a solution of (14), in benzene and in
Benzylselenothiophen-3-carbonyl chloride (8) exhibited
quite remarkable physical properties, being resistant to
aqueous hydrolysis conditions for several hours; indeed (8)
required heating to reflux in water to effect full conversion
into the parent carboxylic acid. In addition, (8) could be puri-
fied by flash chromatography on silica, and required
overnight reflux or prolonged reaction times at room tem-
perature with butylamine in benzene to afford a respectable
yield (76%) of the corresponding amide (9). These interest-
ing observations are discussed in some detail below.
The isomeric amide (12) was prepared from thiophen-2-
carboxylic acid by treatment with 2 equiv. of BuLi followed
by 0.5 equiv. of dibenzyl diselenide (Scheme 2) to afford 3-
benzylselenothiophen-2-carboxylic acid (10) together with
the unwanted isomer, 5-benzylselenothiophen-2-carboxylic
a water-cooled reaction vessel, was irradiated with a 250 W
low-pressure mercury lamp (white light) following our pre-
6
viously published procedure, none of the expected 2-
butylthieno[3,2-d]isoselenazol-3(2H)-one (6; R = Bu) was
isolated. Instead, t.l.c. analysis of the crude reaction mixture
revealed a significant spot of identical R to the starting
F
amide (9); indeed (9) was recovered in near quantitative
yield after workup and chromatography. Interestingly, when
6
the reaction was repeated in (D )benzene and the crude
1
mixture immediately examined by H n.m.r. spectroscopy,
the characteristic signal corresponding to the amide proton in
(9) (ꢀ 7.0) was notably absent. Once again, workup and chro-
matography provided starting material (9) in excellent
recovery.
*
†
‡
2-Thioxo-1,2-dihydropyridin-1-yl 2-benzylselenobenzenecarboximidates (3).
We have reported previously that amide (9) fails to provide the corresponding PTOC carbamate under standard condition. See ref. 7.
1
Imidate esters (14) and (16) exhibited signals in the ꢀ 6.5–7.8 region of their H n.m.r. spectra, typical of PTOC esters in general. See ref. 14.

Novel Analogues of Ebselen
279
reasoning, similar resonance structures may be expected to
contribute to stabilization of (12).
Avery similar resonance picture can be drawn for the acid
chloride (8) with contributor (21) providing significant sta-
bility; the lack of reactivity of (8) reported above would
follow naturally from such a resonance description.
If the radical (22) derived from (9), and that (23) derived
from (12), were also locked in conformations not conducive
to ring-closure, then intermolecular attack at the sulfur atom
in another molecule of the precursor (14) or (16) would be
expected to become the dominant pathways available to
(
22) and (23) (Scheme 5). Under these circumstances, the
product of reaction would be the unstable pyridylthio amide
e.g. (15)] which would return the starting amide (9) or (12)
[
upon workup.
When the isomeric amide (12) was subjected to the con-
ditions described above, the PTOC imidate ester (16) was also
obtained as a thick green oil. Subsequent irradiation in
benzene and workup as described above, once again,
afforded only recovered starting material (12) (Scheme 3).
What is the origin of the observed failure of esters (14)
and (16) to afford the isoselenazolones (6) and (7) (R = Bu)
under conditions which proved successful for the preparation
of the Ebselen analogues (1)? We believe the answer to this
question rests with the conformational properties of amides
(9) and (12) and the radicals derived from them.
We suggest that structures (18)–(20) contribute signifi-
cantly (Scheme 4) to the overall resonance stability of 17. It
is clear that these contributors impose considerable restricted
rotation about the C 3–C(carbonyl) bond in (9). Hypervalent
sulfur species not dissimilar to (20) have been proposed pre-
viously as intermediates in peroxide-mediated decomposi-
In order to provide support for the argument presented
above, the structure of amide (9) was determined by single-
crystal X-ray analysis. Full X-ray structural data for (9) have
16
been published previously, and indicated significant
1
5
tion reactions involving sulfides. Through identical
contact between the selenium atom and the carbonyl carbon.
Indeed the O–Se separation of 2.836 Å ‘lies between the sum
1
6
of the relevant covalent and van der Waals radii’,
indicating a ‘weak interaction similar to that observed for
2
-methylseleno-N-phenylbenzamide and 2-triphenylstannyl-
1
7
seleno-N-phenylbenzamide’.
Unfortunately, the isomeric amide (12) failed to provide a
crystal suitable for X-ray crystallographic analysis. We
1
8
therefore turned to ab initio molecular orbital calculations
to provide further insight. The structures of 2-methyl-
selenothiophen-3-carboxamide (24) and its isomer (25),
model compounds for (9) and (12), were optimized at the
B3LYP/LANL2DZ level of theory,* the results of which are dis-
played in Fig. 1.
*
Geometry optimizations were performed using standard gradient techniques at the B3LYP level of theory using the RHF method and the LANL2DZ
pseudopotential basis set. Further single-point MP2 calculations were performed on the B3LYP-optimized structures. All calculations were performed
on Compaq DS10 servers. For standard techniques, see ref. 19.

2
80
M. J. Laws et al.
Fig. 1. B3LYP/LANL2DZ-optimized structures of 2-(methylseleno)thiophen-3-carboxamide (24) and of
-(methylseleno)thiophen-2-carboxamide (25).
3
Inspection of Fig. 1 reveals that, consistent with the X-ray
benzene under reflux, 2-alkylthieno[2,3-d]isoselenazol-
i
t
data for (9), B3LYP/LANL2DZ calculations predict that the
O–Se separation in (24) is only 2.824 Å, well within the sum
of the relevant covalent and van der Waals radii and indica-
tive of weak bonding. Not surprisingly, a similar close dis-
tance (2.857 Å) is calculated for amide (25). In addition,
Mulliken population analyses of the molecular wavefunc-
tions associated with (24) and (25) indicate that a bonding
interaction exists between the carbonyl oxygen and the sele-
nium atom in each structure. B3LYP overlap populations of
3(2H)-ones (7; R = Me, Pr , Bu ) were isolated in 10, 65 and
73% yield respectively after flash chromatography
(Scheme 6). The low yield of the methyl-substituted product
(7; R = Me) most likely reflects the significant levels of
impurities present in the starting diselenide (13; R = Me).
Unfortunately, the phenyl-substituted amide (13; R = Ph)
proved to be insoluble in most organic solvents; conse-
quently, treatment of (13; R = Ph) with benzoyl peroxide in
6
benzene or chlorobenzene under reflux afforded none of the
0
.023 and 0.027 for (24) and (25) respectively are consistent
required 2-phenylthieno[2,3-d]isoselenazol-3(2H)-one (7; R
= Ph).* Attempted reaction in tetrahydrofuran, dimethyl-
formamide or dimethyl sulfoxide resulted in a complex
mixture of products as evidenced by t.l.c. or H n.m.r. spec-
troscopic analysis.
with a bond order of about 10% in each case.
MP2/LAN2DZ//B3LYP/LANL2DZ (single-point) calculations
provide values of 0.011 and 0.014 for (24) and (25) respec-
tively.
1
Peroxide-Mediated Decomposition of Diselenides:
Preparation of 2-Alkylthieno[2,3-d]isoselenazol-
3
(2H)-ones
During our recent studies into the preparation of Ebselen
6
analogues, we demonstrated that diselenides (5) undergo
peroxide-mediated decomposition in the presence of
benzoyl peroxide to afford a variety of substituted isoselena-
zolones (1) in 76–85% yield. This process is likely to be
ionic in nature.20 With this in mind, a series of substituted
In order to provide conclusive evidence as to the nature of
the compounds in question, the structures of the three 2-
alkylthieno[2,3-d]isoselenazol-3(2H)-ones (7) prepared in
this study were determined by single-crystal X-ray analysis,
the results of which are displayed in Fig. 2.† It is interesting
3
,3Ј-diselenobis(N-alkylthiophencarboxamides) (13; R =
i
t
Me, Pr , Bu , Ph) were prepared in about 50% yield by inser-
tion of elemental selenium into the carbon–lithium bond in
i
t
the corresponding lithiated amides (Scheme 2). In the case of
to note that compounds (7; R = Pr , Bu ) both crystallize with
two independent molecules in the asymmetric unit; in both
cases the two independent molecules differ only very
slightly with respect to the conformation about the N–C(6)
i
(
13; R = Me, Pr ), purification by flash chromatography fol-
lowed by recrystallization failed to provide the diselenides
free from unidentifiable contaminants. In these cases and in
subsequent experiments the crude reaction mixture was not
subjected to attempted purification before further use.
To our delight, when the crude diselenides (13; R = Me,
i
bond. Thus in (7; R = Pr ) the Se–N–C(6)–C(7) dihedral
angle is –86.3(5) and –73.0(5) for the two molecules, while
t
in (7; R = Bu ) the Se–N–C(6)–C(9) dihedral angle is –9.5(6)
i
t
Pr , Bu ) were reacted with benzoyl peroxide (1.0 equiv.) in
and –4.7(6) for the two molecules. These small differences
*
†
We also attempted to use di-t-butyl peroxide in chlorobenzene under reflux, as reported for the synthesis of Ebselen, without success. See ref. 6.
An Accessory Publication consisting of crystal and refinement data, non-hydrogen and hydrogen atom parameters, anisotropic displacement
parameters, bond lengths and angles, torsion angles, and structure factors is available (until 31 December 2005) from the Australian Journal of
Chemistry, P.O. Box 1139, Collingwood, Vic. 3066.

Novel Analogues of Ebselen
281
Fig. 2. Molecular structure and crystallographer’s atom numbering schemes for: (a) 2-methylthieno[2,3-d]isoselenazol-3(2H)-one (7; R = Me);
i
(
b) the two independent molecules of 2-isopropylthieno[2,3-d]isoselenazol-3(2H)-one (7; R = Pr ); (c) the two independent molecules of 2-t-butyl-
t
thieno[2,3-d]isoselenazole-3(2H)-one (7; R = Bu ).
can be attributed to different packing environments sur-
rounding the two molecules in each case.
We are currently examining the biological properties of
isoselenazoles (7) and expect to report our findings in due
course.
(3×40 ml), the combined extracts washed with saturated NaCl, dried
MgSO ) and the solvent removed in vacuum. The residue (3 g) was
dissolved in CH Cl (40 ml), dimethylformamide (1 drop) and pyridine
500 ꢁl) were added and the reaction flask was flushed with nitrogen.
Oxalyl chloride (500 ꢁl) was added dropwise with stirring. The
mixture was stirred overnight, the solvent removed in vacuum,
benzene (30 ml) and butylamine (3.0 ml, 30 mmol) were added slowly
and the resulting solution was heated to reflux overnight.
Dichloromethane (30 ml) was added, the resultant solution washed
(
4
2
2
(
Experimental
Experimental equipment and procedures are as described previ-
ously.7
with 10% HCl (3×30 ml), saturated NaHCO
NaCl (2×30 ml), dried (MgSO ) and the solvent removed in vacuum.
The residue was separated by flash chromatography (5% ethyl
acetate/petrol) to obtain, as the band of higher R , the title compound
3
(3×30 ml), saturated
4
3
-Benzylseleno-N-butylthiophen-2-carboxamide (12)
Butyllithium (14 ml of a 2.2 M solution in cyclohexane) was added
F
1
dropwise, under nitrogen, to a solution of thiophen-2-carboxylic acid
1.98 g, 15 mmol) in dry tetrahydrofuran (c. 20 ml) at –78°. After stir-
(12) as a pale oil (1.54 g, 29%). H n.m.r. ꢀ 0.89, m, 3H; 1.36, m, 2H;
1.48, m, 2H; 3.29, m, 2H; 4.01, s, 2H; 7.00, d, J 5.1 Hz, 1H; 7.15, m,
6H; 7.38, d, J 4.9 Hz, 1H. High-resolution mass spectrum m/z
(
ring for 30 min, dibenzyl diselenide (5.13 g, 15 mmol) in tetrahydro-
furan (20 ml) was added dropwise with stirring. The mixture was stirred
at –78° for 30 min, warmed to room temperature and stirred for 1 h. The
mixture was poured into water (c. 60 ml) and washed with ether (3×40
ml) and acidified with conc. HCl. The product was extracted into ether
183.0718 (C
9
H
13NOS fragment requires 183.0718).
was assigned to be 5-benzylseleno-N-
The product of lower R
F
butylthiophen-2-carboxamide and was isolated as a yellow solid (0.34
1
g, 6%). H n.m.r. ꢀ 0.89, m, 3H; 1.36–1.48, m, 4H; 3.41, m, 2H; 4.06, s,

2
2
82
M. J. Laws et al.
H; 5.85, d, J 4.9 Hz, 1H; 6.91, d, J 3.7 Hz, 1H; 7.1–7.3, m, 6H. High-
X-Ray Crystallographic Study
resolution mass spectrum m/z 183.0720 (C
83.0718).
9
H13NOS fragment requires
Data were collected [at 293(2) K] on an Enraf Nonius CAD4
diffractometer; monochromatized Mo Kꢂ (ꢃ 0.71069 Å) radiation was
used, 2° < ꢄ < 50°. Unit cell dimensions were determined from 25 accu-
rately centred reflections 24° < ꢄ < 30°. Three check reflections moni-
tored every 120 min during data collection showed no significant
1
Preparation of N-Isopropylthiophen-2-carboxamide
A mixture of thiophen-2-carboxylic acid (6.51 g, 0.05 mol) and
thionyl chloride (7.3 ml, 0.1 mol) was heated under reflux until the evo-
lution of gas had ceased. The excess thionyl chloride was removed at
reduced pressure and the crude acid chloride was added to a solution of
isopropylamine (6.0 g, 0.1 mol) in dichloromethane (15 ml). The result-
ing solution was stirred at room temperature for 10 h, after which time
21
variation. The structures were solved by direct methods (SHELXS-86)
22
and refined by full-matrix least-squares methods (SHELX-97).
23
Analytical absorption corrections were applied (SHELX-76). Thermal
ellipsoid plots (Fig. 2) were drawn with ZORTEP and represent 30%
24
ellipsoids.
3
it was washed with saturated NaHCO , water and saturated NaCl. The
Crystal data for (7; R = Me).
6 5
C H NOSSe, M 218.1, ortho-
organic layer was dried (MgSO ) and the solvent removed in vacuum.
4
rhombic, space group Pbca, a 8.5098(9), b 11.7147(8), c 14.365(2)
The crude product was recrystallized from ethyl acetate/hexane to
afford the title compound as colourless crystals (6.44 g, 76%), m.p.
3
–1
Å, V 1432.0(3) Å , Z 8, ꢁ 5.46 mm , maximum and minimum trans-
mission 0.48 and 0.44 respectively, 1251 reflections measured (1251
1
8
38–140° (Found: C, 56.7; H, 6.5; N, 8.0. C H11NOS requires C, 56.8;
unique), final R
Crystal data for (7; R = Pr ).
space group P2 /n, a 9.797(2), b 8.872(3), c 21.921(4) Å, ꢆ 99.11(2)°,
1
[I > 2ꢅ(I)] 0.0361, wR
2
0.0774.
1
H, 6.6; N, 8.3%). H n.m.r. ꢀ 1.23, d, 6H, J 6.6 Hz; 4.23, m, 1H; 6.07,
br s, 1H; 7.03, m, 1H; 7.42, dd, 1H, J 5.1, 1.2 Hz; 7.50, dd, 1H, J 3.2,
3
i
8 9
C H NOSSe, M 246.2, monoclinic,
1
1
3
.0 Hz. C n.m.r. ꢀ 22.7, 41.9, 127.4, 129.5, 139.5, 161.1.
3
–1
V 1881.3(8) Å , Z 8 (two molecules per asymmetric unit), ꢁ 4.16 mm ,
maximum and minimum transmission 0.39 and 0.15 respectively, 3309
Preparation of 3,3Ј-Diselenobis(N-alkylthiophen-2-
carboxamides) (13)
reflections measured (3258 unique), final R
1
[I > 2ꢅ(I)] 0.0535, wR
2
0
.1272.
General protocol. To a solution of the N-alkylthiophen-2-carbox-
amide (10.0 mmol) in dry tetrahydrofuran (70 ml) was added a solution
of butyllithium (11 ml, 2.0 M, in cyclohexane). After stirring at 0° for 30
min, finely divided selenium powder (0.79 g, 10.0 mmol) was added in
one portion. The reaction mixture was stirred for 3 h at room tempera-
ture after which time it was poured into a solution of potassium ferri-
cyanide (3.29 g, 10.0 mmol) in water (50 ml) and the mixture stirred
overnight. The mixture was neutralized with 10% HCl and extracted
with dichloromethane (3×). The combined organic layers were dried
Crystal data for (7; R = But).
C H11NOSSe, M 260.2, monoclinic,
9
1
space group P2 /c, a 9.279(2), b 11.795(2), c 19.931(2) Å, ꢆ 90.60(2)°,
3
–1
V 2181.2(6) Å , Z 8 (two molecules per asymmetric unit), ꢁ 3.60 mm ,
maximum and minimum transmission 0.44 and 0.33 respectively, 4073
reflections measured (3820 unique), final R
.0966.
1 2
[I > 2ꢅ(I)] 0.0401, wR
0
Acknowledgments
(
MgSO
4
) and the solvent was removed in vacuum. The residue was sep-
We thank the Australian Research Council for financial
support, and the China Scholarship Council for a scholarship
to S.-L. Zheng.
arated by flash chromatography (1: 4 ethyl acetate/hexane) to afford the
required diselenide (13) of sufficient purity for further use.
3
,3Ј-Diselenobis(N-phenylthiophen-2-carboxamide) (13; R = Ph)
(1.64 g, 58%) had m.p. 233–235° (ethanol/tetrahydrofuran) (Found: C,
4
5
7.0; H, 2.9; N, 5.0. C22
H
16
N
2
O
2
S
2
Se
2
requires C, 47.0; H, 2.9; N,
References
1
.0%). H n.m.r. (Me
2
SO) ꢀ 7.09, m, 1H; 7.34, m, 2H; 7.41, d, 1H, J 3.6
1
7
7
Schewe, T., Gen. Pharmacol., 1995, 26, 1153; Reich, H. J., and
Hz; 7.68, m, 1H; 7.92, d, 1H, J 3.9 Hz; 10.31, br s, 1H. Se n.m.r.
Jasperse, C. P. J., J. Am. Chem. Soc., 1987, 109, 5549; Müller, A.,
Cadenas, E., Graf, P., and Sies, H., Biochem. Pharmacol., 1984, 33,
(
Me
2
SO) ꢀ 509.
,3Ј-Diselenobis(N-t-butylthiophen-2-carboxamide) (13; R = Bu )
1.31 g, 50%) had m.p. 150–153° (Found: C, 41.4; H, 4.7; N, 5.5.
t
3
3
241; Wendel, A., Fausel, M., Safayhi, H., Tiegs, G., and Otter, R.,
(
1
Biochem. Pharmacol., 1984, 33, 3241.
Jacquemin, P. V., Christiaens, L. E., and Renson, M. J., Tetrahedron
Lett., 1992, 33, 3863.
C
18
H
24
N
2
O
2
S
2
Se
2
requires C, 41.4; H, 4.6; N, 5.4%). H n.m.r. ꢀ 1.48, s,
2
3
1
3
1
1
8H; 5.98, br s, 2H; 7.27, m, 4H. C n.m.r. ꢀ 28.9, 52.3, 126.9, 130.0,
32.0, 132.8, 161.7. Se n.m.r. (Me SO) ꢀ 457.
2
7
7
Demello, M. A. R., Flodstrom, M., and Eizirik, D. L., Biochem.
Pharmacol., 1996, 52, 1703; Hattori, R., Yui, Y., Shinoda, E., Inoue,
R., Aoyama, T., Masayasu, H., Kawai, C., and Sasayama, S., Jpn J.
Pharmacol., 1996, 72, 191; Hattori, R., Inoue, R., Sase, K., Eizawa,
H., Kosuga, K., Aoyama, T., Masayasu, H., Kawai, C., Sasayama,
S., and Yui, Y., Eur. J. Pharmacol.—Mol. Pharmacol., 1994, 267,
R1; Zembowicz, A., Hatchett, R. J., Radziszewski, W., and
Gryglewski, R. J. J., J. Pharmacol. Exp. Ther., 1993, 267, 1112.
Cembrzynskanowak, M., Szklarz, E., and Inglot, A. D., Interferon
Cytokine Res., 1997, 17, 609; Tiegs, G., Kusters, S., Kunstle, G.,
Hentze, H., Kiemer, A. K., and Wendel, A. J., J. Pharmacol. Exp.
Ther., 1998, 287, 1098; Gao, J. X., and Issekutz, A. C., Int. J.
Immunopharmacol., 1994, 16, 279.
Preparation of 2-Alkylthieno[2,3-d]isoselenazol-3(2H)-ones (7)
General protocol. The required crude diselenide (13) (1.0 mmol)
and benzoyl peroxide (0.35 g, 1.1 mmol) were heated to reflux under
nitrogen until t.l.c. indicated the absence of starting material. The reac-
tion mixture was diluted with dichloromethane and then washed with
3
saturated NaHCO and saturated NaCl. The organic layer was dried
(
MgSO ) and the solvent removed in vacuum. The residue was purified
4
4
by flash chromatography (2: 3 ethyl acetate/hexane) to afford the title
compounds as crystalline solids as described below.
t
2
-t-Butylthieno[2,3-d]isoselenazol-3(2H)-one (7; R = Bu ) (0.38 g,
7
3%) had m.p. 195–196° (Found: C, 41.5; H, 4.2; N, 5.4. C
9
H
11NOSSe
1
requires C, 41.5; H, 4.3; N, 5.4%). H n.m.r. ꢀ 1.65, s, 9H; 7.16, d, 1H,
J 5.0 Hz; 7.64, d, 1H, J 5.0 Hz. C n.m.r. ꢀ 28.9, 59.4, 121.7, 130.2,
1
5
6
7
1
3
Anon., Drugs Future, 1995, 20, 1057.
Fong, M. C., and Schiesser, C. H., J. Org. Chem., 1997, 62, 3103.
Fong, M. C., Laws, M. J., and Schiesser, C. H., Aust. J. Chem.,
7
7
33.5, 136.4, 163.0. Se n.m.r. ꢀ 901.
-Isopropylthieno[2,3-d]isoselenazol-3(2H)-one (7;
Pri)
2
R =
1
995, 48, 1221.
(
0.32 g, 65%) had m.p. 139–140° (Found: C, 39.0; H, 3.7; N, 5.6.
8
9
0
1
Esker, J. L., and Newcomb, M., J. Org. Chem., 1994, 59, 2779.
Angus, J. A., Schiesser, C. H., and Venn, M. K., unpublished data.
Engman, L., Laws, M. J., Malmström, J., Schiesser, C. H., and
Zugaro, L. M., J. Org. Chem., 1999, 64, 6764.
Eur. Pat. EP44971; U.S. Pat. 4352799; Ger. Pats DE3515272,
DE3515273.
8 9
C H NOSSe requires C, 39.0; H, 3.7; N, 5.7%). H n.m.r. ꢀ 1.36, d, 6H,
1
3
J 5.4 Hz; 4.68, m, 1H; 7.39, d, 1H, J 4.8 Hz; 7.67, d, 1H, J 4.8 Hz.
C
1
n.m.r. ꢀ 22.2, 45.5, 123.1, 127.0, 131.5, 138.8, 161.5. 77Se n.m.r. ꢀ 888.
2
-Methylthieno[2,3-d]isoselenazol-3(2H)-one (7; R = Me) (0.05 g,
0%) had m.p. 245–247° (Found: C, 33.0; H, 2.3; N, 6.5. C NOSSe
requires C, 33.0; H, 2.3; N, 6.4%). H n.m.r. ꢀ 3.27, s, 3H; 7.37, d, 1H,
11
1
6 5
H
1
1
2
1
3
Lambert, C., Hilbert, M., Christiaens, L., and Dereu, N., Synth.
Commun., 1991, 21, 85.
J 4.8 Hz; 7.84, d, 1H, J 4.8 Hz. C n.m.r. ꢀ 31.17, 124.6, 126.9, 132.5,
7
7
1
40.6, 163.1. Se n.m.r. ꢀ 925.

Novel Analogues of Ebselen
283
1
1
3
4
Esker, J. L., and Newcomb, M., J. Org. Chem., 1993, 58, 4933.
Barton, D. H. R., Crich, D., and Motherwell, W. B., Tetrahedron,
J., Baker, J., Stewart, J. J. P., Head-Gordon, M., Gonzalez, C., and
Pople, J. A., Gaussian 94, Revision B.3, Gaussian Inc., Pittsburgh,
Pennsylvania, 1995.
1
985, 41, 3901.
1
1
5
6
19
Pryor, W. A., and Bickley, H. T., J. Org. Chem., 1972, 37, 2885.
Gable, R. W., Laws, M. J., and Schiesser, C. H., Acta Crystallogr.,
Sect. C, 1997, 53, 641.
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Sect. C, 1996, 52, 1886.
Frisch, M. J., Trucks, G. W., Schlegel, H. B., Gill, P. M. W., Johnson,
B. G., Robb, M. A., Cheeseman, J. R., Keith, T., Petersson, G. A.,
Montgomery, J. A., Raghavachari, K., Al-Laham, M. A.,
Zakrzewski, V. G., Ortiz, J. V., Foresman, J. B., Peng, C. Y., Ayala,
P. Y., Chen, W., Wong, M. W., Andres, J. L., Replogle, E. S.,
Gomperts, R., Martin, R. L., Fox, D. J., Binkley, J. S., Defrees, D.
Hehre, W. J., Radom, L., Schleyer, P. v. R., and Pople, J. A., ‘Ab
Initio Molecular Orbital Theory’ (John Wiley: New York 1986).
Laws, M. J., Ph.D. Thesis, The University of Melbourne, 1999.
Sheldrick, G. M., SHELXS-86, Program for the Solution of Crystal
Structures, University of Göttingen, Germany, 1990.
Sheldrick, G. M., SHELXL-97, Program for the Refinement of Crystal
Structures, University of Göttingen, Germany, 1997.
Sheldrick, G. M., SHELX-76, Program for Crystal Structure
Determination, University of Cambridge, England, 1976.
Zsolnai, L., ZORTEP, An Interactive ORTEP Program, University of
Heidelberg, Germany, 1994.
2
0
1
1
7
8
21
22
2
2
3
4