Highly efficient synthesis and antioxidant capacity of N-substituted benzisoselenazol-3(2H)-ones

Article abstract of DOI:10.1039/c4ra08631g

A new, general one step synthesis of N-substituted benzisoselenazol-3(2H)-ones based on the reaction of o-iodobenzamides with lithium diselenide, is described. A series of alkyl and aryl derivatives was obtained in high yields (up to 98%). Their GPx-like antioxidant activity, tested by NMR, showed a significantly higher activity than ebselen.

Full text of DOI:10.1039/c4ra08631g

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Highly efficient synthesis and antioxidant capacity
of N-substituted benzisoselenazol-3(2H)-ones†
Cite this: RSC Adv., 2014, 4, 48959
*
Agata J. Pacuła, Jacek S´cianowski and Krzysztof B. Aleksandrzak
Received 13th August 2014
Accepted 29th September 2014
DOI: 10.1039/c4ra08631g
www.rsc.org/advances
A new, general one step synthesis of N-substituted benzisoselenazol- Organoselenium compounds can be easy transformed into
3(2H)-ones based on the reaction of o-iodobenzamides with lithium various reactive nucleophilic, electrophilic or radical reagents,
diselenide, is described. A series of alkyl and aryl derivatives was e.g. addition of electrophilic selenium reagents to the double
obtained in high yields (up to 98%). Their GPx-like antioxidant activity, bonds and selenocyclization reactions were used to create new
tested by NMR, showed a significantly higher activity than ebselen.
carbon–carbon, carbon–oxygen and carbon–nitrogen bonds.
Chiral reagents make possible a stereoselective reactions.6 Our
previous work was focused on the synthesis of optically active
terpenyl selenols, selenides, diselenides, and their applications
in asymmetric synthesis.7 Methodology presented in this work
enables to obtain compounds exhibiting benecial physiolog-
ical and catalytic activities, and can not only be applied as
catalysts in biological cycles but also as reagents in organic
synthesis, fullling the requirements of green chemistry.8
Since the late 80's, four main methods for the synthesis of
benzisoselenazol-3(2H)-ones have been developed (Scheme 1).
Oxidative stress is the cause of many frequently occurring
diseases, involving the dysfunction of the cardiovascular
system, neurodegeneration, aging, and cell damage leading to
oncogenesis.1 It can be dened as the imbalance between the
production and destruction of free radicals in cells. Reactive
oxygen species (ROS) cause damage that leads to apoptotic
death. An increase of this process causes uncontrolled cell
proliferation. Aerobic cells possess catalytic antioxidant systems
as a natural defence against reactive oxygen and nitrogen
species. Glutathione peroxidase (GPx), a selenoenzyme that
reduces the excess of hydroperoxides, plays a major role in this
process. Although the known GPx mimic, N-phenyl benzisose-
lenazol-3(2H)-one 1 (ebselen),2 has been thoroughly studied, the
search for more effective and less toxic analogues is currently
one of the main topics of organoselenium chemistry.3
Selenium possesses several signicant properties.4 This
essential micronutrient exhibits “insulin-like” activity
–
increased glucose and lipid metabolism is correlated with low
selenium blood levels. Furthermore, it decreases the risk of
cardiovascular disease by eliminating lipid peroxidation and
inuencing the role of inammatory mediators. In mood
disorders it protects neurons from oxidative stress and toxic
effects of heavy metals by complexing them.5
Despite the biological importance of selenium, another
advantage is its higher nucleophilicity and acidity than sulfur
and ability to form long, weaker bonds with carbon atoms.
Department of Organic Chemistry, Faculty of Chemistry, Nicolaus Copernicus
University, 7 Gagarin Street, 87-100 Torun, Poland. E-mail: jsch@chem.umk.pl; Fax:
+48 566542477; Tel: +48 566114532
† Electronic supplementary information (ESI) available: Experimental procedures
and full characterization data. See DOI: 10.1039/c4ra08631g
Scheme 1 Synthetic approaches to benzisoselenazol-3(2H)-one 1.
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The reaction of N-substituted benzamides 2 with n-butyl- hypothesis N-cyclohexyl substituted diselenide 7 was prepared.
lithium, selenium powder and copper bromide as an oxidant Its reactions with LiOH, NaI, and a mixture of LiOH/NaI were
was reported by Engman et al.9 Another methodology is the carried out. Only the mixture gave the N-cyclohexyl benzisose-
formation of the Se–N bond by the diazotization of anthranilic lenazol-3(2H)-on 8 (Scheme 3).
acid 3 and reaction with sodium diselenide that enables to form
On the other hand the reaction of 7 with commercial avail-
dibenzoic acid o-diselenide. This intermediate reacts with thi- able KIO3 also gave 8.
onyl chloride to generate the corresponding chloride 4, which
The developed method was efficient for a variety of
reacts with aniline to give 1. This route is most commonly used, substrates including alkyl derivatives with short 9 and 10, long
however, the yields, are only moderate.10 Two new methods were 11 or branched chains 12 and 13, also cyclic 8, and with addi-
proposed by Kumar and co-workers.11,12 In both cases tional aryl function 14 and 15, also aryl derivatives with the
N-substituted o-iodobenzamide 5 is used as a substrate. In the naphthyl 16 and 17, anthryl 18 and phenyl group substituted
copper-catalyzed synthesis the catalyst is formed by the reaction with nitro- 19, bromo- 20, iodo- 21 and methoxy-22 substitu-
of 1,10-phenantroline with copper iodide. In the presence of ents14 (Scheme 4). Compounds 1, 8, 10, 13, 14, 20, 21 have
potassium carbonate as a base, CuI/L catalyses the Se–N established biological activity.15
coupling.11 In the second method the substrate is treated with
The evaluation of the antioxidant activity was based on the
KSeOtBu formed in situ by the reaction of tBuOK with selenium method proposed by Iwaoka and co-workers with 10% of the
(2 : 1). The authors report that benzisoselenazol-3(2H)-ones are catalyst.16 Benzisoselenazol-3(2H)-ones were oxidized by
obtained in higher yields due to the fact that in the previous hydrogen peroxide to seleninic acid which catalyses the trans-
method the catalyst was hard to separate from the product.12
formation of dithione 23, bearing two thiol groups to a disul-
In this paper we present, an efficient method for the de–dithiotreitol 24. The reaction rate was measured by 1H
synthesis of N-substituted benzisoselenazol-3(2H)-ones, and NMR analysis. The result can show not only the antioxidative
their antioxidant properties. Our starting material sodium potential of the compound but also the ability to catalyse the
selenide, was prepared in situ from sodium borohydride and formation of S–S bonds in proteins.17 The decrease in the
elemental selenium.7e We assumed that applying NaSeNa as a concentration of the substrate was measured aer 3, 5, 15, 30
reagent in the formation of the Se–N bond would enable us to and 60 minutes for each compound (see ESI†). Comparing to
synthesise benzizoselenazol-3(2H)-ones. However, only the iodo ebselen, the alkyl analogues with one to four carbon chains
substituent was replaced by the hydrogen atom, and 6 was exhibit higher reactivity, and when long and branched N-
obtained (Scheme 2). A similar effect was observed when substituted derivatives are used the reaction rate decreases
sodium sulde was used.13 Then sodium diselenide, formed signicantly – the concentration of the substrate aer 60
from sodium hydroxide and elemental selenium in the presence minutes is still about 80–90%. Among aryl analogues only those
of hydrazine hydride was used.7b In this case the only product with the p-nitro, p-iodo and p-methoxy phenyl group are
was 1. The efficiency of the reaction using lithium, sodium and stronger catalysts than ebselen. The p-iodo substituted deriva-
potassium hydroxides was also tested. The highest yield was tive enables to nish the reaction aer 5 minutes. For the most
obtained when lithium hydroxide was applied (Scheme 2). This active compounds 15, 19, 21, 22 the test was performed with 5%
method for the synthesis of lithium diselenide is unknown in of the catalyst (Fig. 1).
the literature. We have also tested the reaction of N-phenyl
2-chloro- and 2-bromobenzamide with in Li2Se2. Only 2-bromo- 3(2H)-ones are much stronger catalysts than ebselen. Using
benzamide yielded 21% of 1. catalysts containing N-phenyl group substituted in para posi-
According to this study, the obtained benzisoselenazol-
We assume, that the rst step is the formation of diselenide tion with NO2 or I 21, 19, aer 2 hours we have observed 100%
7 by the reaction of sodium diselenide with o-iodobenzamide.
Then the present in the reaction mixture NaI/LiOH transforms
the diselenide to the corresponding seleninic acid, and the
elimination of water gives ebselen derivatives. To conrm our
Scheme 3 Plausible mechanism of the benzizoselenazolo-3-(2H)-
Scheme 2 Reaction of o-iodobenzamide with Na2Se and Na2Se2.
48960 | RSC Adv., 2014, 4, 48959–48962
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Notes and references
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