Convenient synthesis, characterization and GPx-like catalytic activity of novel ebselen derivatives

Article abstract of DOI:10.1002/ejoc.200400326

The synthesis and characterization of benzisochalcogenazolones (ebselen derivatives 16-21) is described. The synthesis of 16-21 was achieved by treating the bromo precursors 11-13 with an appropriate dilithium dichalcogenide. The synthesis of benzisoselenazolones 16 and 18 was also accomplished by an alternative route, that is, by treating the corresponding methoxymethyl selenides 22 and 23 with 1 equiv. of bromine. The synthesis of methoxymethyl selenides 22 and 23 was accomplished by lithiation of the bromo precursors followed by treatment with bis(methoxymethyl) diselenide. The benzisoselenazolones 16 and 17 were characterized by single-crystal X-ray techniques. The GPx-like catalytic activities of compounds 16-18 and 21 were determined by using the coupled reductase assay. Compound 16 was found to be less active than ebselen 8 whereas compounds 17 and 18 were more active than ebselen in this assay. Compound 21 showed a 1.5-fold higher activity than its selenium analogue 17. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400326

FULL PAPER
Convenient Synthesis, Characterization and GPx-Like Catalytic Activity of
Novel Ebselen Derivatives
Sanjio S. Zade,[a] Snigdha Panda,[a] Santosh K. Tripathi,[a] Harkesh B. Singh,*[a] and
Gotthelf Wolmershäuser[b]
Keywords: Ebselen / Nonbonding interactions / Benzisochalcogenazolone / TeϪN heterocycles / ortho-Lithiation
The synthesis and characterization of benzisochalcogenazol- elenide. The benzisoselenazolones 16 and 17 were character-
ones (ebselen derivatives 16−21) is described. The synthesis
of 16−21 was achieved by treating the bromo precursors
11−13 with an appropriate dilithium dichalcogenide. The
ized by single-crystal X-ray techniques. The GPx-like cata-
lytic activities of compounds 16−18 and 21 were determined
by using the coupled reductase assay. Compound 16 was
synthesis of benzisoselenazolones 16 and 18 was also ac- found to be less active than ebselen 8 whereas compounds
complished by an alternative route, that is, by treating the 17 and 18 were more active than ebselen in this assay. Com-
corresponding methoxymethyl selenides 22 and 23 with 1 pound 21 showed a 1.5-fold higher activity than its selenium
equiv. of bromine. The synthesis of methoxymethyl selenides
22 and 23 was accomplished by lithiation of the bromo pre-
cursors followed by treatment with bis(methoxymethyl) dis-
analogue 17.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
corresponding benzisochalcogenazolones by air oxidation,
followed by disproportionation.
One of our groups reported a series of organochalcogens
that are stabilized by an ortho-coordinating group.[7] As a
continuation of this work, we have started a systematic
study of the synthesis, structural characterization and reac-
tions of organochalcogens that have two ortho-coordinating
groups. Our efforts to synthesize the desired organochal-
cogen derivatives with two alkyl/arylcarbamoyl groups by
treating N,NЈ-dialkyl/diphenyl-2-bromo-5-tert-butylisoph-
thalamide with Li2E2 (E ϭ S, Se, Te), interestingly, afforded
ebselen derivatives.
Ebselen (8) [2-phenylbenzisoselenazol-3(2H)-one], its de-
rivatives and analogues[8] are good glutathione peroxidase
mimics, antiinflammatory, antiatherosclerotic, anticancer
and antimicrobial agents, as well as immunostimulants,
cytokine inducers and nitric acid synthase inhibitors.[9]
The chemistry of organoselenium derivatives stabilized
by intramolecular nonbonding interactions (Se···X; X ϭ N,
O, S) has attracted considerable interest because of their
applications as (a) chiral reagents in asymmetric synthesis,[1]
(b) ligands in the isolations of monomeric MOCVD precur-
sors,[2] (c) ligands for chiral/achiral catalysis[3] and (d) gluta-
thione peroxidase mimics.[4] In recent studies, Tiecco[1g] and
Wirth[1h] and their co-workers reported that even better en-
antioselectivity could be obtained in asymmetric methoxy-
selenenylation of double bonds by introducing substituents
with specific heteroatoms at all the ortho positions to sel-
enium in diaryl diselenide (1 and 2). Intramolecular non-
bonding interactions by two heteroatoms in organoselen-
ium compounds also allow the isolation of rather unstable
selenenium cations, for example, the cation 3 is stabilized by
chelation with two tertiary amino groups.[5] More recently,
Kersting and DeLion reported the synthesis of chalcogenols
4Ϫ7 by ortho-lithiation and selenium insertion, followed by
hydrolysis with HCl.[6] The reaction, however, afforded the
[a]
Department of Chemistry, Indian Institute of Technology,
Bombay Powai, Mumbai 400 076, India
Fax: (internat.) ϩ 91-22-2572-3480
E-mail: chhbsia@chem.iitb.ac.in
[b]
Fachbereich Chemie, Universität Kaiserslautern,
Postfach 3049, Kaiserslautern 67653, Germany
Fax: (internat.) ϩ 49-(0)631-205-2187
E-mail: wolmersh@chemie.unk-kl.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2004, 3857Ϫ3864
DOI: 10.1002/ejoc.200400326
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. S. Zade, S. Panda, S. K. Tripathi, H. B. Singh, G. Wolmershäuser
FULL PAPER
Although ebselen is a major GPx mimic, its synthesis has complete at 100 °C in DMF within 1 h, whereas at reflux
been a challenge[10] since it was first prepared in 1924.[11] In in THF it took 6 h for the reaction to go to completion.
the earliest and most direct approach, 2,2Ј-diselenodiben-
A similar procedure for the synthesis of benzisochalcog-
enazolone heterocycles by ortho-lithiation of dialkylisoph-
thalamide, selenium insertion, followed by oxidation
zoic acid was converted into a chloroselenenylbenzoyl chlo-
ride which was treated with aniline to give ebselen.[10c] The
(Scheme 3) has been reported by Kersting and DeLion.[6]
The mechanism involves the disproportionation of dichal-
cogenides to give an equimolar mixture of benzisochalcog-
enazolones and the corresponding selenol. However, reac-
tions of dimethyl/diethylisophthalamide did not lead to the
desired products probably because of the low solubility of
the intermediate trilithium salts. The formation of the eb-
selen framework in this case probably occurs by the dispro-
portionation of diselenide 14 to give benzisoselenazolone 16
as proposed by Kersting and DeLion.[6] The steric bulk may
be the extra driving force for this mechanistic pathway.
most expedient method was reported by Engman and
Hallberg[10d] and utilized a one-pot procedure in which
benzanilide was ortho-lithiated, treated with selenium pow-
der and then ring-closed by a cuprous bromide mediated
oxidative procedure. A free-radical synthesis of ebselen has
been achieved by intramolecular homolytic substitution
with amidyl radicals.[10e,10f] It has been further observed
that the ebselen derivative 9 with an ortho-coordinating
nitro group is more active as a GPx mimic than the parent
ebselen (8).[12] We report here a new general synthetic ap-
proach to 2-alkyl/phenyl-5-tert-butyl-7-(alkyl/phenylcarba-
moyl)benzisochalcogenazol-3(2H)-one (substituted ebselen
derivatives) using a one-pot procedure.
To examine the general applicability of this synthetic
method, the reactions of Li2Se2 were carried out with 12
and 13. To our delight, the reactions led to good yields of
17 and 18. Benzisothiazolones 19 and 20 were similarly syn-
thesized in good yields by the treatment of 11 and 12 with
dilithium disulfide. When 11Ϫ13 were treated with dilith-
ium ditelluride, the expected benzisotellurazolones were ob-
tained in very low yields with the debrominated isophthal-
amides as the predominant products; only the benzisotellur-
azolone 21 was isolated and characterized by spectroscopic
methods. Only one report on the synthesis and character-
ization of benzisotellurazolones has appeared in the litera-
ture.[6]
Results and Discussion
Synthesis
N,NЈ-Dialkyl/diphenyl-2-bromo-5-tert-butylisophthal-
amides 11Ϫ13 were prepared by treating 2-bromo-5-tert-
butylisophthalic acid (10)[13] with thionyl chloride, followed
by the reaction with the corresponding amines without isol-
ating the bis(acyl chloride) (Schemes 1 and 2). To prepare
diselenide 14, the well-established route of lithiation, sel-
enium insertion, followed by oxidation, was attempted.[7]
Aryl methoxymethyl selenides are known to afford the
The lithiation of 11 with 3 equiv. of nBuLi afforded a dark corresponding arylselenenyl bromides on treatment with
brown slurry; however, insertion of selenium into the CϪLi bromine (1 equiv.) solution,[1e] which, in turn, can be con-
bond was not successful and the final isolated product was verted into diaryl diselenides by reduction with sodium
the debrominated diamide 15 (Scheme 1).
borohydride. With this in mind, the methoxymethyl selen-
The other well-known approach to diaryl diselenides in- ides 22 and 23 were synthesized by lithiation of 11 and 13,
volves the treatment of alkali metal diselenides with aryl respectively, with 3 equiv. of nBuLi, followed by treatment
bromides.[14] Surprisingly, treatment of compound 11 with with 1 equiv. of bis(methoxymethyl) diselenide (Scheme 2).
dilithium diselenide in THF at reflux did not afford the ex- The yields of the selenides 22 and 23 were poor. The iso-
pected diselenide 14. Instead, the novel substituted ebselen lation of pure selenides also proved quite difficult due to
16 was obtained in high yield (Scheme 2). The reaction was contamination of the debrominated products. Interestingly,
Scheme 1
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Eur. J. Org. Chem. 2004, 3857Ϫ3864

Synthesis, Characterization and GPx-Like Catalytic Activity of Novel Ebselen Derivatives
FULL PAPER
Scheme 2. Reagents and conditions: (i) SOCl2, reflux, 4 h; (ii) RNH2, CH2Cl2, 0 °C Ǟ room temp., 12 h; (iii) Li2Se2, THF/DMF, reflux,
0.5Ϫ1 h; (iv) Li2S2, THF, reflux, 12Ϫ15 h; (v) Li2Te2, THF/DMF, reflux, 1 h; (vi) 3 equiv. nBuLi, THF, Ϫ45 °C; (vii) (CH3OCH2)2Se2,
THF, 0 °C Ǟ room temp.; (viii) Br2, CHCl3, 0 °C Ǟ room temp.
Scheme 3
the treatment of selenides 22 and 23 with 1 equiv. of bro- shifts of related compounds.[10e,10f] The 125Te NMR spec-
mine again afforded the corresponding benzisoselenazol- trum of benzisotellurazolone 21 exhibits a signal at δ ϭ
ones 16 and 18 instead of the expected selenenyl bromides. 1435 ppm, which compares well with the chemical shift of
the related TeϪN heterocycle benzisotellurazole (24) (δ ϭ
1589 ppm).[15]
Spectroscopic Studies
The 1H NMR spectra of diamides 11Ϫ13 indicate the
symmetric nature of these compounds in solution. The aro-
matic protons of the tetrasubstituted phenyl ring of 11Ϫ13
appear as a singlet whereas they appear as two different
signals in the spectra of benzisoselenazolones 16Ϫ18. In the
case of 16, these signals were obtained as two doublets with
meta coupling (J ϭ 2 Hz). The protons of the two methyl
groups in 17 appear as a singlet and doublet, whereas they
In the mass spectra (ES-MS and FAB) of the benziso-
are present as a doublet in the spectrum of the precursor chalcogenazolones, the base peaks correspond to the molecu-
diamide 12. In a similar way, the tertiary protons of the lar ion peaks; this indicates the high stability of these com-
isopropyl groups of 18 appear as a septuplet and multiplet pounds under mass spectrometric conditions. Molecular
whereas the spectrum of diamide 13 exhibits only one sep- ion peaks were not observed for compounds 22 and 23.
tuplet for these two protons. These observations support However, the base peaks correspond to [M Ϫ CH2OCH3]ϩ,
the formation of the benzisoselenazolone rings. Similar ob- which indicates the lability of the methoxymethyl group at-
servations were obtained for the sulfur (19, 20) and tel- tached to the selenium atom in 22 and 23. The IR spectra
lurium analogues (21). The aromatic protons of the tetra- of compounds 11Ϫ13 and 16Ϫ23 exhibit peaks at
substituted phenyl ring of selenides 22 and 23 appear as a 1600Ϫ1660 and 1520Ϫ1560 cmϪ1, which correspond to the
singlet, which indicates the symmetric nature of these two amide I and amide II bands, respectively. However, the car-
selenides.
bonyl band of the open-chain secondary amide cannot be
77Se NMR spectroscopy serves as an important tool for distinguished from that of the ring amide.
monitoring these reactions as the chemical shifts of the
selenium signal in benzisoselenazolones have a specific
range.[10e,10f] The 77Se NMR spectra of benzisoselenazol-
Crystal Structures of Compounds 16 and 17
An ORTEP view of compound 16 is shown in Figure 1,
ones 16Ϫ18 exhibit signals at δ ϭ 907, 880 and 822 ppm, and selected bond lengths and bond angles are listed in
respectively, which are well within the range of chemical Table 1. The coordination geometry around the Se atom is
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S. S. Zade, S. Panda, S. K. Tripathi, H. B. Singh, G. Wolmershäuser
FULL PAPER
Figure 1. Molecular structure of compound 16
˚
V-shaped with a bond angle of 84.33(10)°, which is similar
to that reported for the parent ebselen [2-phenylbenziso-
selenazol-3(2H)-one] [85.8(1)°],[16] 7-nitro-2-phenylbenziso-
selenazol-3(2H)-one (9) [85.49(17)°],[17] 2-propionylbenziso-
selenazol-3(2H)-one (25) [85.19(19)°][16] and 7-isopro-
pylcarbamoyl-2-isopropylbenzisoselenazol-3(2H)-one (26)
[84.46(18), 84.74(18)°].[6b] The geometry around the ring ni-
trogen atom is nearly planar with bond angles of
Se(1)ϪN(1)ϪC(7) ϭ 115.87(16)°, Se(1)ϪN(1)ϪC(8) ϭ
119.98(17)° and C(7)ϪN(1)ϪC(8) ϭ 124.1(2)°. These val-
ues compare well with the corresponding values for 9, 25
Table 1. Selected bond lengths [A] and bond angles [°] of com-
pound 16
Se(1)ϪC(1)
Se(1)ϪN(1)
Se(1)···O(2)
1.856(2)
1.916(2)
2.435(2)
C(1)ϪSe(1)ϪN(1)
C(7)ϪN(1)ϪC(8)
C(7)ϪN(1)ϪSe(1)
C(8)ϪN(1)ϪSe(1)
84.33(10)
124.1(2)
115.87(16)
119.98(17)
dination geometry around Se is V-shaped with a bond angle
of 84.91(14)°. The geometry around the ring nitrogen atom
is nearly planar with bond angles of Se(1)ϪN(1)ϪC(7)
˚
and 26. The C(1)ϪSe(1) [1.856(2) A] distance is slightly
ϭ
116.4(3)°, Se(1)ϪN(1)ϪC(8)
ϭ
121.1(3)° and
˚
shorter than the sum of the Pauling covalent radii (1.91 A)
C(7)ϪN(1)ϪC(8) ϭ 122.4(3)°. The Se(1)···O(2) distance
˚
and the Se(1)ϪN(1) [1.916(2) A] distance is slightly longer
˚
[2.553(3) A] is significantly shorter than the sum of the van
˚
than the sum of the Pauling covalent radii (1.87 A). How-
˚
der Waals radii of these two atoms (3.4 A).
ever, these values are similar to those reported for 9, 25 and
26. Of particular interest is the intramolecular interaction
between the selenium atom and the oxygen atom of the car-
GPx-Like Catalytic Activity
boxamide group. Interestingly, the Se(1)···O(2) distance
The catalytic activities were studied by using the coupled
[2.435(2) A] is significantly shorter than the sum of the van reductase assay.[4a] The GPx activities of compounds 16Ϫ18
˚
˚
der Waals radii of these two atoms (3.4 A) and is slightly and 21 are listed in Table 3. Organoselenium compounds
˚
˚
shorter than that observed in 9 [2.562(4) A], 25 [2.806(4) A] that have intramolecularly coordinating basic amino groups
and 26 [2.453(3), 2.496(3) A].
˚
have been studied extensively as Se···N nonbonding interac-
An ORTEP view of compound 17 is shown in Figure 2, tions are known to enhance the catalytic capacity of these
and selected bond lengths and bond angles are listed in antioxidant agents.[4] The enhancement of the activities of
Table 2. The compound is isostructural with 16. The coor- compounds 17 and 18 relative to that of ebselen can be
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Eur. J. Org. Chem. 2004, 3857Ϫ3864

Synthesis, Characterization and GPx-Like Catalytic Activity of Novel Ebselen Derivatives
FULL PAPER
Figure 2. Molecular structure of compound 17
˚
Table 2. Selected bond lengths [A] and bond angles [°] of com-
Conclusion
pound 17
In conclusion, the reaction of dilithium diselenide/disulf-
ide/ditelluride with N,NЈ-dialkyl/diphenyl-2-bromo-5-tert-
butylisophthalamide affords the novel ebselen derivatives 2-
alkyl/phenyl-7-(alkyl/phenylcarbamoyl)-5-tert-butylbenziso-
chalcogenazol-3(2H)-one. The yields of the benzisothiazo-
lones and benzisoselenazolones were very good; however,
the benzisotellurazolones were obtained in poor yields.
Thus, this method provides a convenient alternative strategy
to the synthesis of such compounds. Alternatively, benziso-
selenazolones can be prepared via methoxymethyl selenides
by the reaction with bromine. Benzisoselenazolones 17 and
18 showed higher GPx-like activity than ebselen, whereas
compound 16 showed very poor activity. Benzisotellurazol-
one 21 is 1.5 times more active than the selenium ana-
logue 17.
Se(1)ϪC(1)
Se(1)ϪN(1)
Se(1)···O(2)
1.859(3)
1.884(3)
2.553(3)
C(1)ϪSe(1)ϪN(1)
C(7)ϪN(1)ϪC(8)
C(7)ϪN(1)ϪSe(1)
C(8)ϪN(1)ϪSe(1)
84.91(14)
122.4(3)
116.4(3)
121.1(3)
ascribed to the Se···O intramolecular interaction. However,
16 showed significantly lower activity which could be attri-
buted to its poor solubility. The reactivity toward hydroper-
oxides usually increases as one descends the chalcogen
group. Generally, tellurium compounds are more active
than the selenium analogues[18] and in this case the activity
of compound 21 was 1.5 times greater than that of its sel-
enium analogue.
Table 3. GPx activities of compounds 16Ϫ18 and 21
Experimental Section
Compound
GPx activities[a]
General Procedures: All reactions were carried out under nitrogen
or argon using standard vacuum-line techniques. Solvents were
purified by standard procedures and were freshly distilled prior to
use. Melting points were recorded in capillary tubes and are uncor-
Ebselen (8)
4.96
1.84
15.71
7.06
16
17
18
21
1
rected. H (299.94 MHz), 13C (75.42 MHz), 77Se (57.22 MHz) and
23.73
125Te (94.75 MHz) spectra were recorded in CDCl3 with a Varian
VXR 300S or Bruker AMX 500 spectrometer at room temperature.
Chemical shifts are referenced to TMS (1H, 13C) as internal stand-
[a]
50 µ of Se equiv., 1.2 m of tBuOOH. Measured as the con-
sumption of NADPH [µ·minϪ1].
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ard and to Me2Se (77Se) and Me2Te (125Te) as external standards.
Elemental analyses were performed with a CarloϪErba model 1106
elemental analyzer. IR spectra were recorded as KBr pellets with a
Thermo Nicolet Avatar 320 FTIR spectrometer. FAB mass spectra
were recorded at room temperature with a JEOL SX 102 DA-6000
mass spectrometer. ESI MS mass spectra were recorded at room
reaction mixture turned colorless during the reflux period. After
cooling to room temperature, the reaction mixture was poured into
a solution of brine (100 mL). The resulting pale yellow precipitate
was collected by filtration and dried. It was further purified on a
silica gel column by using ethyl acetate/petroleum ether (1:9) as
eluent. Yield: 0.76 g, 85%. M.p. 304Ϫ306 °C. 1H NMR (300 MHz,
temperature with a Q-Tof micro (YA-105) micromass spectrometer. [D6]DMSO, 25 °C): δ ϭ 1.46 (s, 9 H), 7.25 (m, 2 H), 7.45 (t, J ϭ
Dilithium dichalcogenides,[14] 2-bromo-5-tert-butylisophthalic
acid[13] and bis(methoxymethyl) diselenide[1e] were synthesized ac-
cording to literature methods.
6.0 Hz, 4 H), 7.70 (m, 4 H), 8.15 (d, J ϭ 2.0 Hz, 1 H), 8.86 (d, J ϭ
2.0 Hz, 1 H), 11.07 (s, 1 H) ppm. 13C NMR (400 MHz, CDCl3, 25
°C): δ ϭ 31.3, 35.2, 122.0, 124.0, 125.4, 125.6, 125.7, 127.7, 128.1,
128.9, 129.3, 129.4, 137.2, 137.7, 140.1, 151.3, 164.0, 165.2 ppm.
77Se NMR (500 MHz, CDCl3, 25 °C): δ ϭ 907.2 ppm. IR (KBr):
ν˜ ϭ 3321 νNϪH, 1663, 1526 νCϭO cmϪ1. MS: m/z (%) ϭ 451 (100)
[M]ϩ, 435 (10), 358 (7). C24H22N2O2Se (449.32): calcd. C 64.16, H
4.94, N 6.23; found C 63.80, H 5.13, N 6.52.
2-Bromo-5-tert-butyl-N,NЈ-diphenylisophthalamide (11): 2-Bromo-
5-tert-butylisophthalic acid (10) (1.51 g, 5 mmol) was refluxed with
thionyl chloride (3.6 mL, 50 mmol) for 4 h. Unreacted thionyl chlo-
ride was removed by distillation and any remaining traces were
removed under vacuum. The liquid obtained was dissolved in
CH2Cl2 (50 mL) and transferred to a dropping funnel mounted on
a two-necked 250-mL flask. The flask was charged with aniline
(1.2 g, 12 mmol), dissolved in 50 mL of CH2Cl2. The solution in
the dropping funnel was added to the aniline solution at 0 °C. The
resulting solution was warmed to room temperature and stirred
overnight. The reaction mixture was washed with 10% aqueous
NaOH (2 ϫ 50 mL), water (2 ϫ 50 mL) and 10% HCl (2 ϫ 50 mL).
The organic layer was washed with water, dried with sodium sulfate
and concentrated to give a white solid which was purified by crys-
tallization from dichloromethane. Yield 2.15 g, 98%. M.p. 254Ϫ256
°C. 1H NMR (300 MHz, [D6]DMSO, 25 °C): δ ϭ 1.34 (s, 9 H),
7.11 (t, J ϭ 10.0 Hz, 2 H), 7.35 (t, J ϭ 10.0 Hz, 4 H), 7.58 (s, 2
H), 7.73 (d, J ϭ 10.0 Hz, 4 H), 10.54 (s, 2 H) ppm. 13C NMR
(400 MHz, CDCl3 ϩ [D6]DMSO, 25 °C): δ ϭ 30.5, 34.2, 112.7,
119.5, 123.5, 125.8, 128.1, 138.1, 139.6, 150.5, 165.9 ppm. IR
(KBr): ν˜ ϭ 3320 νNϪH, 1664, 1522 νCϭO cmϪ1. MS: m/z (%) ϭ 451
(100) [M]ϩ, 358 (50). C24H23BrN2O2 (451.36): calcd. C 63.87, H
5.14, N 6.21; found C 64.11, H 5.13, N 6.07.
5-tert-Butyl-2-methyl-7-(methylcarbamoyl)benzisoselenazol-3(2H)-
one (17): Compound 17 was prepared from 12 (0.65 g, 2 mmol)
and Li2Se2 (2.5 mmol) according to the procedure described for
the preparation of 16. The crude solid was recrystallized from a
concentrated chloroform solution of the compound. Yield: 0.53 g,
1
81%. M.p. 240 °C (dec.). H NMR (400 MHz, CDCl3, 25 °C): δ ϭ
1.27 (s, 9 H), 3.12 (d, J ϭ 4.8 Hz, 3 H), 3.41 (s, 3 H), 7.9 (br., 1
H), 8.11 (s, 1 H), 8.20 (s, 1 H) ppm. 13C NMR (400 MHz, CDCl3,
25 °C): δ ϭ 27.2, 30.8, 31.4, 35.0, 125.0, 125.3, 127.9, 129.5, 138.2,
150.8, 167.0, 167.4 ppm. 77Se NMR (300 MHz, CDCl3, 25 °C): δ ϭ
880.5 ppm. IR (KBr): ν˜ ϭ 3276 νNϪH, 1619, 1553 νCϭO cmϪ1. MS:
m/z (%) ϭ 326 (100) [M]ϩ. C14H18N2O2Se (325.18): calcd. C 51.71,
H 5.58, N 8.61; found C 51.07, H 5.27, N 8.05.
5-tert-Butyl-2-isopropyl-7-(isopropylcarbamoyl)benzisoselenazol-
3(2H)-one (18): Compound 18 was prepared from 13 (0.77 g,
2 mmol) and Li2Se2 (2.5 mmol) according to the procedure de-
scribed for the preparation of 16. The crude solid was recrystallized
from a concentrated acetonitrile solution of the compound. Yield:
0.55 g, 71%. M.p. 244Ϫ246 °C. 1H NMR (400 MHz, CDCl3, 25
°C): δ ϭ 1.34 (d, J ϭ 6.6 Hz, 6 H), 1.35 (s, 9 H), 1.40 (d, J ϭ
6.0 Hz, 6 H), 4.36 (m, 1 H), 3.78 (sept, J ϭ 6.0 Hz, 1 H), 6.87 (br.
s, 1 H), 7.88 (s, 1 H), 8.24 (s, 1 H) ppm. 13C NMR (400 MHz,
CDCl3, 25 °C): δ ϭ 22.7, 23.5, 31.4, 35.1, 43.0, 46.2, 125.2, 125.9,
127.5, 130.5, 138.2, 150.5, 165.8 ppm. 77Se NMR (500 MHz,
CDCl3, 25 °C): δ ϭ 822.6 ppm. IR (KBr): ν˜ ϭ 3254 νNϪH, 1599,
1540 νCϭO cmϪ1. MS: m/z (%) ϭ 383 (100) [M]ϩ, 341 (37), 299
(17). C18H26N2O2Se (381.28): calcd. C 56.70, H 6.87, N 7.35; found
C 56.19, H 6.56, N 6.92.
2-Bromo-5-tert-butyl-N,NЈ-dimethylisophthalamide (12): Com-
pound 12 was prepared from 10 (1.51 g, 5 mmol), thionyl chloride
(3.6 mL, 50 mmol) and methylammonium chloride (1.36 g,
20 mmol) according to the procedure described for the preparation
1
of 11. Yield: 1.28 g, 78%. M.p. 246Ϫ248 °C. H NMR (400 MHz,
CDCl3, 25 °C): δ ϭ 1.29 (s, 9 H), 3.00 (d, J ϭ 4.8 Hz, 6 H), 6.13
(br., 2 H), 7.44 (s, 2 H) ppm. 13C NMR (400 MHz, CDCl3, 25 °C):
δ ϭ 26.8, 31.0, 34.9, 112.7, 127.2, 139.3, 151.5, 168.9 ppm. IR
(KBr): ν˜ ϭ 3231 νNϪH, 1639, 1547 νCϭO cmϪ1. MS: m/z (%) ϭ 327
(100) [M]ϩ, 295 (7), 238 (37). C14H19BrN2O2 (327.22): calcd. C
51.39, H 5.85, N 8.56; found C 51.82, H 5.72, N 8.23.
5-tert-Butyl-2-phenyl-7-(phenylcarbamoyl)benzisothiazol-3(2H)-one
(19): Compound 11 (0.9 g, 2 mmol) in THF (25 mL) was added
to a stirred solution of Li2S2 [2.5 mmol, prepared by adding 1 
superhydride solution in THF (2.5 mL) to sulfur powder (0.08 g,
2.5 mmol) at room temperature] in THF. The reaction mixture was
refluxed for 12 h, cooled to room temperature, washed with water
(20 mL) and extracted with CHCl3 (3 ϫ 25 mL). The combined
organic layers were dried with Na2SO4 and concentrated to give a
white solid which was purified on a silica gel column by using ethyl
acetate/petroleum ether (1:9) as eluent. Yield: 0.6 g, 67%. M.p. 260
2-Bromo-5-tert-butyl-N,NЈ-diisopropylisophthalamide (13): Com-
pound 13 was prepared from 10 (1.51 g, 5 mmol), thionyl chloride
(3.6 mL, 50 mmol) and isopropylamine (0.89 g, 15 mmol) accord-
ing to the procedure described for the preparation of 11. Yield:
1.68 g, 78%. M.p. 248Ϫ250 °C. 1H NMR (400 MHz, CDCl3, 25
°C): δ ϭ 1.28 (d, J ϭ 6.4 Hz, 12 H), 1.30 (s, 9 H), 4.28 (m, 2 H),
5.71 (d, J ϭ 7.2 Hz, 2 H), 7.43 (s, 2 H) ppm. 13C NMR (400 MHz,
CDCl3, 25 °C): δ ϭ 22.5, 31.0, 34.8, 42.3, 112.5, 126.8, 139.4, 151.5,
167.2 ppm. IR (KBr): ν˜ ϭ 3244 νNϪH, 1636, 1535 νCϭO cmϪ1. MS:
m/z (%) ϭ 383 (100) [M]ϩ. C18H27BrN2O2 (383.33): calcd. C 56.40,
H 7.10, N 7.31; found C 56.23, H 6.97, N 7.02.
1
°C (dec.). H NMR (400 MHz, CDCl3, 25 °C): δ ϭ 1.46 (s, 9 H),
7.23 (t, J ϭ 7.2 Hz, 1 H), 7.31 (t, J ϭ 7.6 Hz, 1 H), 7.44 (m, 4 H),
7.71 (d, J ϭ 7.2 Hz, 2 H), 7.76 (d, J ϭ 7.6 Hz, 2 H), 8.08 (s, 1 H),
8.36 (s, 1 H), 8.47 (br., 1 H) ppm. 13C NMR (400 MHz, CDCl3,
25 °C): δ ϭ 31.2, 35.2, 121.7, 124.2, 124.5, 125.0, 125.8, 126.2,
126.7, 128.4, 128.9, 129.5, 137.4, 137.6, 138.6, 150.2, 162.7,
164.3 ppm. IR (KBr): ν˜ ϭ 3260 νNϪH, 1656, 1541 νCϭO cmϪ1. MS:
m/z (%) ϭ 403 (100) [M]ϩ. C24H22N2O2S (402.52): calcd. C 71.62,
H 5.51, N 6.96; found C 71.89, H 5.62, N 7.03.
5-tert-Butyl-2-phenyl-7-(phenylcarbamoyl)benzisoselenazol-3(2H)-
one (16): A brown solution of Li2Se2 (2.5 mmol) was prepared by
treating lithium with an equivalent amount of selenium powder in
the presence of a catalytic amount of naphthalene in THF. Diamide
11 (0.902 g, 2 mmol) and DMF (10 mL) were added to this stirred
solution. The resulting solution was refluxed for 1 h. The brown
3862
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3857Ϫ3864

Synthesis, Characterization and GPx-Like Catalytic Activity of Novel Ebselen Derivatives
FULL PAPER
5-tert-Butyl-2-methyl-7-(methylcarbamoyl)benzisothiazol-3(2H)-one Determination of GPx-Like Activity: The catalytic activities were
(20): Compound 20 was prepared from 12 (0.65 g, 2 mmol) and
determined by the coupled reductase assay.[4a] The reaction was
Li2S2 (2.5 mmol) according to the procedure described for the prep-
carried out at 25 °C in a solution (1 mL) containing 0.1  potass-
aration of 19, but with a reflux time of 10 h. The crude solid was ium phosphate buffer (pH ϭ 7.3), 1 m DTPA, 1 m GSH, 0.1 m
recrystallized from a concentrated acetonitrile solution of the com- NADPH, 0.6 U of GSH reductase and 50 µ of the test com-
pound. Yield: 0.34 g, 61%. M.p. 208Ϫ210 °C. 1H NMR (400 MHz, pound. The reaction was initiated by the addition of 1.2 m tert-
CDCl3, 25 °C): δ ϭ 1.37 (s, 9 H), 3.10 (d, J ϭ 4.4 Hz, 3 H), 3.44 butyl hydroperoxide. As soon as the glutathione was oxidized to
(s, 3 H), 7.0 (br., 1 H), 7.89 (s, 1 H), 8.22 (s, 1 H) ppm. 13C NMR the corresponding disulfide, the hydroperoxide was enzymatically
(400 MHz, CDCl3, 25 °C): δ ϭ 27.1, 30.3, 31.6, 35.2, 124.1, 125.6, reduced. The activity was determined by UV/Vis spectrophotome-
126.4, 126.7, 139.4, 149.8, 165.3, 166.8 ppm. IR (KBr): ν˜ ϭ 3239 try by monitoring the decrease of NADPH absorption at λ ϭ
νNϪH, 1630, 1538 νCϭO cmϪ1. MS: m/z (%) ϭ 279 (100) [M]ϩ.
340 nm . Appropriate controls were run in the absence of enzyme
C14H18N2O2S (278.37): calcd. C 60.41, H 6.52, N 10.06; found C and were subtracted from the test samples. The activity is expressed
60.72, H 6.58, N 10.41.
in terms of the consumption of NADPH (µ·minϪ1).
X-ray Crystallography: The diffraction measurements for com-
pounds 16 and 17 were performed at room temperature using
graphite-monochromated Mo-Kα radiation (λ ϭ 0.7107 A). The
5-tert-Butyl-2-methyl-7-(methylcarbamoyl)benzisotellurazol-3(2H)-
one (21): Compound 21 was prepared from 12 (0.65 g, 2 mmol)
and Li2Te2 (2.5 mmol) according to the procedure described for the
preparation of 16. The crude solid was purified on a silica gel col-
umn using petroleum ether (boiling range 60Ϫ80 °C)/CHCl3 (4:1)
˚
structures were solved by direct methods and full-matrix least-
squares refinement on F2 (program SHELXL-97).[19] Hydrogen
atoms were localized by geometrical means. A riding model was
chosen for refinement. The isotropic thermal parameters of the H
atoms were fixed at 1.5 times (CH3 groups) or 1.2 times U(eq)
(ArϪH) of the corresponding C atom. Some details of the refine-
ment are given in Table 4. Crystallographic data for the structures
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publications
CCDC-237094 and -237095. Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK [Fax: (internat.) ϩ 44-1223/336-033; E-mail:
deposit@ccdc.cam.ac.uk].
1
as eluent. Yield: 0.03 g, 4%. H NMR (500 MHz, CDCl3, 25 °C):
δ ϭ 1.18 (s, 9 H, tBu), 3.16 (d, J ϭ 4.0 Hz, 3 H), 3.25 (s, 3 H), 8.12
(s, 1 H), 8.22 (s, 1 H), 8.42 (br., 1 H) ppm. 13C NMR (400 MHz,
CDCl3, 25 °C): δ ϭ 27.5, 31.5, 31.9, 35.0, 125.1, 127.3, 128.3, 129.5,
134.6, 152.1, 168.2, 169.7 ppm. 125Te NMR (300 MHz, CDCl3, 25
°C): δ ϭ 1535.3 ppm. IR (KBr): ν˜ ϭ 3295 νNϪH, 1646, 1553 νCϭO
cmϪ1. MS: m/z (%) ϭ 376 (100) [Mϩ]. C14H18N2O2Te (373.90):
calcd. C 44.99, H 4.48, N 7.48; found C 45.47, H 4.87, N 7.24.
4-tert-Butyl-2,6-bis(phenylcarbamoyl)phenyl Methoxymethyl Selen-
ide (22): A 1.6  solution of nBuLi (1.9 mL, 3 mmol) was added
to a solution of 2-bromo-5-tert-butyl-N,NЈ-diphenylisophthalamide
(11) (0.45 g, 1 mmol) under nitrogen at Ϫ45 °C and warmed to
room temperature. Bis(methoxymethyl) diselenide (0.248 g,
1 mmol) was added to the reaction mixture at 0 °C, which was then
warmed to room temperature and stirred for an additional 0.5 h.
The reaction mixture was washed with water and extracted with
ethyl acetate (2 ϫ 25 mL). The combined organic layers were dried
with sodium sulfate and concentrated under vacuum to give a col-
orless solid which was purified on neutral alumina (chloroform/
petroleum ether, 1:3) and recrystallized from a saturated solution
of acetonitrile. Yield: 0.2 g, 45%. M.p. 218Ϫ220 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ ϭ 1.34 (s, 9 H), 3.22 (s, 3 H), 5.16 (s,
2 H), 7.16 (t, J ϭ 7.3 Hz, 2 H), 7.16 (t, J ϭ 7.9 Hz, 4 H), 7.64 (d,
J ϭ 8.4 Hz, 4 H), 7.67 (s, 2 H), 8.13 (s, 2 H) ppm. 13C NMR
(400 MHz, CDCl3, 25 °C): δ ϭ 31.2, 35.2, 59.0, 117.5, 120.1, 124.7,
126.7, 129.0, 137.9, 144.5, 153.5, 167.5 ppm. 77Se NMR (300 MHz,
CDCl3, 25 °C): δ ϭ 295.0 ppm. IR (KBr): ν˜ ϭ 3288 νNϪH, 1625,
1549 νCϭO cmϪ1. MS: m/z (%) ϭ 451 (100) [M Ϫ CH2OCH3]ϩ,
435 (25), 358 (10). C26H28N2O3Se (495.39): calcd. C 63.04, H 5.70,
N 5.65; found C 62.76, H 5.58, N 5.63.
Table 4. Crystal data and structure refinement for 16 and 17
16
17
Empirical formula
Formula mass
Crystal system
Space group
C24H22N2O2Se
449.40
monoclinic
I2/a
18.5372(11)
12.5770(10)
19.9907(12)
115.284(6)
4214.2(5)
8
C14H18N2O2Se
325.26
monoclinic
P21/n
6.3549(9)
11.0351(10)
19.982(3)
92.497(16)
1399.9(3)
4
˚
a [A]
˚
b [A]
˚
c [A]
β [°]
3
˚
V [A ]
Z
Dcalcd. [Mg·mϪ3
]
1.417
1.804
1.543
2.682
Abs. coeff. [mmϪ1
]
Obsd. reflns. [I Ͼ 2σ]
30780
0.0349
0.0803
4444/0/265
0.900
1717
0.0409
0.0904
14740/0.106/2919
0.86
Final R(F) [I Ͼ 2σ(I)][a]
wR(F2) indices [I Ͼ 2σ(I)]
Data/restraints/parameters
Goodness of fit on F2
4-tert-Butyl-2,6-bis(isopropylcarbamoyl)phenyl Methoxymethyl Sel-
enide (23): Compound 23 was prepared from 13 (0.383 g, 1 mmol),
a 1.6  solution of nBuLi (1.9 mL, 3 mmol) and bis(methoxyme-
thyl) diselenide (0.248 g, 1 mmol) according to the procedure de-
scribed for the preparation of 22. The crude product was purified
on a silica gel column using dichloromethane/ethyl acetate (1:5) as
eluent and recrystallized from a saturated solution of acetonitrile.
Yield: 0.08 g, 21%. M.p. 196Ϫ198 °C. 1H NMR (400 MHz, CDCl3,
25 °C): δ ϭ 1.27 (d, J ϭ 6.8 Hz, 12 H), 1.32 (s, 9 H), 3.33 (s, 3 H),
4.25 (m, 1 H), 5.13 (s, 2 H), 5.05 (d, J ϭ 7.6 Hz, 2 H), 7.48 (s, 2
[a]
2
2
Definitions: R(Fo) ϭ ||Fo| Ϫ |Fc||/|Fo| and wR(Fo ) ϭ {[w(Fo
Ϫ
2 2
2 2
Fc ) ]/ [w(Fc ) }1/2
.
Supporting Information: 1H and 13C NMR spectra of all newly syn-
thesized compounds, 77Se NMR spectra for 16Ϫ18 and 22, 125Te
NMR spectrum of 21 and tables for GPx-like activity of 16Ϫ18
and 21.
Acknowledgments
H) ppm. 13C NMR (400 MHz, CDCl3, 25 °C): δ ϭ 22.7, 31.2, 35.0, We are grateful to the Department of Science and Technology
42.4, 58.7, 76.7, 118.3, 126.2, 144.7, 152.9, 169.1 ppm. IR (KBr): (DST), New Delhi, for funding this work. Additional help from
ν˜ ϭ 3293 νNϪH, 1622, 1544 νCϭO cmϪ1. MS: m/z (%) ϭ 413 (16) [M
the Regional Sophisticated Instrumentation Center (RSIC), Indian
Ϫ Me]ϩ, 383 (100) [M Ϫ CH2OMe]ϩ, 356 (8), 341 (43), 299 (19). Institute of Technology (IIT), Bombay, and the Tata Fundamental
Eur. J. Org. Chem. 2004, 3857Ϫ3864
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3863

S. S. Zade, S. Panda, S. K. Tripathi, H. B. Singh, G. Wolmershäuser
FULL PAPER
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acknowledged. Thanks are also due to the RSIC, Central Drug
Research Institute (CDRI), Lucknow, for providing mass spectra.
S. S. Z. wishes to thank the CSIR, New Delhi, for a fellowship.
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