Straightforward synthesis and antioxidant studies of chalcogenoaziridines

Article abstract of DOI:10.1016/j.tetlet.2016.06.101

Herein we reported the synthesis of chalcogenoaziridines through the introduction of the organoselenium moiety in the aziridine framework through the nucleophilic substitution of the OTs leaving group. In addition, the antioxidant activity, as reflected b

Full text of DOI:10.1016/j.tetlet.2016.06.101

Accepted Manuscript
Straightforward Synthesis and Antioxidant Studies of Chalcogenoaziridines
Rodrigo Borges, Floyd C.D. Andrade, Ricardo S. Schwab, Fernanda S.S. Sousa,
Maurice Neto de Souza, Lucielli Savegnago, Paulo H. Schneider
PII:
S0040-4039(16)30778-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.101
TETL 47828
Reference:
Tetrahedron Letters
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21 June 2016
22 June 2016
Please cite this article as: Borges, R., Andrade, F.C.D., Schwab, R.S., Sousa, F.S.S., Souza, M.N.d., Savegnago, L.,
Schneider, P.H., Straightforward Synthesis and Antioxidant Studies of Chalcogenoaziridines, Tetrahedron
Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.06.101
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Straightforward Synthesis and Antioxidant
Studies of Chalcogenoaziridines
Rodrigo Borges, Floyd C. D. Andrade, Ricardo S. Schwab,* Fernanda S. S. Sousa, Maurice Neto de Souza,
Lucielli Savegnago and Paulo H. Schneider*

1
Tetrahedron Letters
Straightforward Synthesis and Antioxidant Studies of Chalcogenoaziridines
Rodrigo Borges,a Floyd C. D. Andrade,b Ricardo S. Schwab, b,Fernanda S. S. Sousa,c Maurice Neto de
Souza,c Lucielli Savegnagoc and Paulo H. Schneider a,
a Instituto de Química, Universidade Federal do Rio Grande do Sul (UFRGS), UFRGS, P.O. Box 15003, 91501-970, Porto Alegre-RS, Brazil. Fax:+55 51 3308-
7304; Tel: +55 51 3308-9636. E-mail: paulos@iq.ufrgs.br - www.iq.ufrgs.br/schneider
b
Departamento de Química, Universidade Federal de São Carlos, UFSCar, 13565-905, São Carlos, SP, Brazil. +55 (16) 3351-8081; rschwab@ufscar.br
c Grupo de pesquisa em Neurobiotecnologia, Universidade Federal de Pelotas, Pelotas, RS, Brazil. +55 (53) 3275-7350
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein we reported the synthesis of chalcogenoaziridines through the introduction of the
organoselenium moiety in the aziridine framework through the nucleophilic substitution of the
OTs leaving group. In addition, the antioxidant activity, as reflected by free radical scavenging,
was also evaluated. The new seleno aziridine 6a showed more effective antioxidant compared to
other compounds. These findings also suggest that seleno aziridine 6a is a promising antioxidant
and that its activity is not influenced by the presence of the substituents attached into the
aromatic ring.
Available online
Keywords:
Chalcogenoaziridines
Selenium
2009 Elsevier Ltd. All rights reserved.
Aziridines
Antioxidant
Chalcogens
———
 Corresponding author. Tel.: +55 16 3351-8081; e-mail: rschwab@ufscar.br
 Corresponding author. Tel.: +55 51 3308-9636; e-mail: paulos@iq.ufrgs.br

2
Tetrahedron Letters
1. Introduction
for the preparation of novel chiral chalcogenoaziridines. In
addition, the antioxidant activity of these new synthesized
compounds was investigated.
Aziridines are one of the most versatile three-membered ring
systems in modern synthetic chemistry. They have been used as
precursors of many complex molecules;1 once they can easily go
2. Results and Discussion
through
a
regioselective ring-opening reaction whit
nucleophiles.2 Furthermore, an aziridine moiety can be found in
some natural products, and different synthetic compounds of
biological interest.3 In addition, chiral aziridines have been also
applied with success as chiral ligands in asymmetric reactions.4
In keeping with our aim, as the starting point of this study, we
sought an efficient way to prepare the key chiral tosylate
aziridine 5 in a short and high yielding sequence. To accomplish
this task, we used some procedures already described in the
literature, where the amino acid L-serine was first converted into
the respectively amino ester 1 by reacting with MeOH in the
presence of tionyl chloride. Selective protection of the amino
group in 1 as the trityl derivative 2, followed by the treatment of
2 with methanesulphonyl chloride in THF afforded the aziridine
3 in 76% yield.13 The N-tritylaziridine-2-carboxylic ester 3 was
converted into the corresponding N-tritylaziridine-2-ylmethanol 4
using lithium aluminium hydride in THF at room temperature for
24 h with 88% yield. The reaction of the primary hydroxyl group
with p-toluenesulphonyl chloride in the presence of triethylamine
and using 4-dimethylaminopydirine as a catalyst delivered the
desired tosylate 5 in 87% yield (Scheme1).
In the last decades, there has been a growing interest in
developing new methodologies for the preparation of the
aziridinyl systems and in this sense, different heteroatom
substituents, attached to one or both carbon atoms of the ring
have been introduced. Thus, obtaining aziridines, especially
optically active aziridines, has become of great importance in
organic synthesis.5
Moreover, the scope and application of organochalcogen
chemistry have increased tremendously, since this class of
compounds has continued to attract considerable attention due
their biological properties.6 For instance, it has been
demonstrated that organoselenium compounds play an important
role as therapeutic compounds, such as antiviral, anticancer
agents, and in a variety of situations where free radicals are
involved.7 Furhermore, organochalcogens have been widely
studied given their antioxidant activity, which confers
neuroprotection, antiulcer, and antidiabetic properties. Among
organochalogens, selenium containing molecules may be better
nucleophiles,and therefore better antioxidants than classical ones,
thus leading to the necessity to design new synthetic
organoselenium compounds. In this context, antioxidant
pharmacotherapy has emerged as a tool to minimise the
biomolecular damage caused by the attack of free radicals. Based
on the growing interest in the investigation of the
pharmacological and toxicological properties of the
organoselenium compounds, several synthetic methods for the
preparation of selenoaminoacids, selenium-based peptides,
selenium-nucleosides, seleno-carbohydrates and other important
natural compounds derivatives are well established, being that an
area of intensive research.8
O
O
O
(i)
(ii)
HO
OH
HO
Trt
OMe
HO
OMe
NH2
NH
2
NH2.HCl
1
L-serine
O
(iii)
(iv)
(v)
OMe
OH
OTs
N
N
N
Trt
4
5
Trt
Trt
3
Scheme 1. Synthetic strategy to prepare tosylate 5. Reagents and conditions:
(i) MeOH, thionyl chloride, overnight, r.t.; (ii) trityl chloride, triethylamine,
CH2Cl2, , 24 h, r.t.; (iii) MsCl, triethylamine, THF 0oC, then 48 h, 65oC; (iv)
LiAlH4, THF, 24 h, r.t.; (v) TsCl, triethylamine, DMAP, CH2Cl2, 24 h, r.t.
With the required tosylate 5 in hand, we turned our attention
to the introduction of the organoselenium moiety in the aziridine
framework through the nucleophilic substitution of the OTs
leaving group (Table 1). Organoselenium anions were generated
through the reaction of diphenyldiselenide with NaBH4 in a
mixture of 3:1 THF and ethanol, as previously described.14
Surprisingly, under these standard conditions, the desired seleno
aziridine 6a was formed in only 51% yield after 24 h (entry 1).
On the other hand, aziridines have been also used as starting
materials for the synthesis of β-chalcogen amines which are
usually prepared by the regioselective ring opening reaction with
chalcogen nucleophiles, generated by different reducing agents.
Although β-chalcogen amines represents an important class of
compound and were used basically as chiral ligands in different
reactions;9 there are only few examples in the literature reporting
the synthesis of chiral chalcogenoaziridines.10 This fact can be
rationalized by locking at the reactivity of the aziridine ring. This
ring is suitable to react with a variety of nucleophiles due to its
Table 1. Optimization of the reaction conditions for the synthesis
of seleno-aziridine 6a.a
OTs
SePh
PhSeSePh/NaBH4
THF/EtOH (3:1)
N
N
electrophilic nature. In this sense, there is
methodologies for the introduction of nucleophiles on the side
a lack of
Trt
Trt
6a
5
chain, maintaining the aziridine ring intact.
Entry
Time (h)
Temperature (oC)
Yield (%)[b]
Owing to the specific chemical and physical properties of
selenium, the incorporation of this group into aziridines
compounds can strongly affect the activity of these systems.
However, the incorporation of the selenium atom into the side
chain of aziridines is much more restricted, and, as far as we
know, there are only two papers concerning the preparation of
selenoaziridines as sources of aziridinylmethyl radicals.11
1
2
3
24
24
12
r.t.
66
66
51
74
75
a
All reactions were performed in the presence of tosylate 5 (1.0 mmol),
diphenyldisselenide (0.5 mmol) and THF-EtOH (3:1) under nitrogen
atmosphere. [b] Isolated yields.
On account of these aspects and in association with our
ongoing research interest toward organochalcogen chemistry,12
we report herein an efficient and straightforward synthetic route

3
We then tried to conduct the nucleophilic substitution reaction
under different conditions, by increasing the temperature. Under
reflux, an increase in the yield to 74% was obtained (entry 2). By
reducing the reaction time from 24 h to 12 h, no decrease on the
reaction yield was observed (entry 3).
(4-ClPhSe)2
(2,4,6-MePhSe)2
(NafSe)2
4
5
6
7
8
9
6d
6e
6f
66
44
46
23
49
69
71
It is worth noting that the purification step is crucial for the
achievement of the seleno aziridine in good yields. When the
chromatographic column was performed using Silica Gel, the
major product isolated after the purification was the allylamine 7
and none of the desired product 6a was observed.15 By
1
comparison of the H NMR spectra, we could then confirm the
absence of signals referent to the alkene in the crude product
when compared with the 1H NMR of allylamine 7 (see
Supplementary data). Taking this into consideration, we decided
to replace Silica Gel by Aluminium Oxide 90 (Standardised for
column chromatographic adsorption analysis acc. Brochmann),
and to our delight the seleno-aziridine 6a was isolated in good
yield after the purification step (Scheme 2).
(BuSe)2
6g
6h
6i
Aluminium
oxide 90
SePh
SePh
Silica Gel
N
N
NHTrt
Trt
Trt
7
crude product
6a
(PhS)2
Scheme 2. Chromatographic column performed using Silica Gel and
Aluminium oxide 90.
With the optimal condition in hand, we extended the protocol
to additional selenium and even sulphur nucleophiles (Table 2
entry 1-10). The reaction was tolerant to a variety of substituents
at the aromatic ring of the organoselenium moiety, allowing the
preparation of a series of selenoaziridines in moderate and good
yields. The reaction was influenced by electronic effects since
electron-withdrawing groups such as -chloro, -trifluoromethyl in
the aromatic ring afforded better yields (entries 3 and 4)
compared with electron-donating groups, -methyl (entry 2). We
also employed other diselenide sources in this reaction, e.g. alkyl
moiety. For instance, dibuthyl diselenide reacted with tosylate 5,
allowing the preparation of the desired product 6g in low yield
(entry 7). The reaction is also efficient with sulphur nucleophiles,
which resulted in the thioaziridines 6h-j in good yields (entries 8-
10).
(3-CF3PhS)2
(2-ClPhS)2
10
6j
a
All reactions were performed in the presence of tosylate 5 (1.0 mmol),
diaryldisselenide (0.5 mmol) and THF-EtOH (3:1) under nitrogen
atmosphere. [b] Isolated yields.
3. Effect of Chalcogenoaziridines in Lipid Peroxidation
Table 2. Synthesis of selenium and thioaziridines.a
The effect of chalcogenoaziridines in Lipid Peroxidation assay
are given in Table 3. Selenoaziridines 6a, 6c and 6d decreased
the levels of lipid peroxidation at concentrations as low as 50
µM, while compounds 6f and 6g were effective at concentrations
equal or greater than 100 µM. Of these compounds, 6a was the
most potent with the lowest IC50 value (70.6 ± 13.65 µM), while
6e was the least potent (IC50 291.6 ± 202.8 µM). When
thioaziridines were evaluated, compound 6h, was the most
efficient with the highest Imáx value (68,24 ± 20,30) ,, decreasing
the levels of lipid peroxidation at concentrations as low as 10
µM, while compound 6j (87.5± 45.96) was effective at
concentrations equal to or greater than 100 µM. Aziridine
compound was also tested, showing no ability to reduce lipid
peroxidation. This leads us to believe that the addition of
selenium and sulfur to the aziridine structure generates an
increase in the antioxidant potential of the molecule. The potency
of the compounds selenoaziridines, determined by the lowest
IC50, follows the order 6a<6c<6f<6d<6g<6b<6e, and the
compounds thioaziridines 6j≤6h<6i. The results showed that
electronic and steric effects of the substituents attached to the
different positions of the phenyl ring had no significant influence
on the antioxidant activity.
Yield
(%)[b]
Entry
1
RYYR
Product
(PhSe)2
6a
6b
75
31
(4-MePhSe)2
(3-CF3PhSe)2
2
3
6c
78

4
Tetrahedron Letters
Table 3. Antioxidant activity of compounds against lipid peroxidation.
Imax
(%)
Concentration(µM)
IC50
(µM)
Compound
10
50
100
250
500
97.35 ± 3.57
99.0 ± 1.73
83.18 ± 18.41
91.17±9.18
87.02±20.4
80.52±9.88
100±0.0
63.25±5.75**
81.83±28.56
56.78±16.53*
60.84±34.10*
89.83±20.35
69.33±24.44
82.94±20.63
41.59±21.93*
65.79±15.33
58.44±26.65
33.58±12.68***
73.42±23.08
41.10±19.84**
48.17±15.67*
86.29±26.28
38.47±15.68**
53.82±23.63*
41.38±20.33*
61.61±20.91
42.26±23.82*
24.24±17.86***
-
70.6± 13.65
184.3± 190.1
79.0± 43.28
88.25 ± 20.02
291.6± 202.8
80.0± 25.0
116.2± 54.06
89.6± 66.11
107.5± 15.00
87.5± 45.96
74.76 ± 17.86
69.98 ± 9.23
70.04 ± 13.68
65.65 ± 13.39
69.26± 28.43
75.47 ± 3.43
85.49 ± 8.58
68.24 ± 20.30
66.75 ± 17.12
67.49 ± 22.79
6a
6b
6c
6d
6e
6f
6g
6h
6i
-
30.02±9.23*
29.96±13.68**
-
-
29.23±10.57**
-
35.92±34.39*
24.53±3.43***
-
-
14.51±8.58***
61.64±26.28*
63.93±18.3
69.85±21.2
31.76±20.30**
-
-
33.25±17.1**
-
35.31±19.95*
6j
Data are expressed as mean ± SD (n = 4) of % lipid peroxidation; IC50 = concentration (µM) to decrease 50% of lipid peroxidation; Imax = % maximal
inhibition; * denotes p< 0.05; **p< 0.01; ***p< 0.001 when compared to control sample by Student-Newman-Keuls test.
permitted the preparation of a wide range of compounds with a
4. Effect Effect of Selenoaziridines in FRAP
highly modular character. The use of Aluminium Oxide 90, for
the purification of the selenoaziridines, has shown to be crucial in
order to obtain the product. Moreover, to the best of our
knowledge, this is the first time that the antioxidant activity of
chalocogenoaziridines has been reported against a range of free
radicals.
FRAP assay is a SET (singlet electron transformer) method
which is based on the reduction capability of ferric ion (Fe3+) to
ferrous ion (Fe2+) of a test sample.16 Aziridine has the ability to
reduce the ferric ion at the concentration of 100 µM (see Table
4). Compound 6a has the reduce capability at the concentration
of 50 µM. The compounds 6b and 6e reduced the ferric ion at
concentrations of 50-100 µM. The compounds 6d and 6f have the
potential to reduce concentrations of 10-100 µM. Based in these
data, the addition of selenium had the ability to enhance the
reducing potential since the aziridine showed reduction of ferric
ion at the concentration of 100 uM (p <0.01) and the compounds
6d and 6f show a reducing potential in concentration of 10 uM (p
<0.01). All other compounds (Table 3, 6c, 6g, 6h, 6i and 6j) did
not have an effect in this assay. Thus, the best compounds for
reduce ferrous ion are the selenoaziridines 6d and 6f. This
activity may be due to the high electronegativity of the chlorine
attached to the aromatic ring in the compound 6d and the
increase of the size of the aromatic moiety in compound 6f.
Acknowledgments
We gratefully acknowledge to the São Paulo Research
Foundation - FAPESP (2013/06558-3), Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq), INCT-CMN,
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
(CAPES) and Fundação de Amparo à Pesquisa do Estado do Rio
Grande do Sul (FAPERGS).
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Compound
Aziridine
10
50
100
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(a) Godoy, M.; Alberto, E. E.; Paixão, M. W.; Soares, L. A.;
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0.106 ± 0.018
0.215 ± 0.011
0.396 ± 0.09**
0.451 ± 0.032
0.257 ± 0.06
0.315 ± 0.04**
0.158 ± 0.06
0.288 ± 0.02**
1.43 ± 0.32***
0.463 ± 0.14*
-
6a
6b
6d
6e
6f
0.759 ± 0.15***
1.258 ± 0.06***
1.144 ± 0.04***
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(a) Pellissier, H.; Tetrahedron 2010, 66, 1509. (b) Degennaro, L.;
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0.773 ± 0.07***
0.819 ± 0.25***
0.772 ± 0.007***
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1.315 ± 0.05***
*
Data are expressed as mean ± SD (n = 3) of absorbance at 593 nm. p< 0.05;
**p<0.01; ***p< 0.001 when compared with control sample by Student–
Newman-Keuls.
5. Conclusions
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In summary, we have developed a new and efficient method
for the synthesis of chalcogenoaziridines. These compounds were
prepared via a concise and flexible route, in good yields, which

5
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HIGHLIGHTS
 Synthesis
and
of
complete
chiral
characterization
new
chalcogenoaziridines;
 General method for the synthesis of
selenium and sulfur derivatives;
 Development of a efficient method for
the
synthesis
of
functionalized
aziridines, without ring opening;
 Evaluation of the antioxidant activity of
the new chiral chalcogenoaziridines;
 Evaluation of the effect of the chalcogen
atom against their antioxidant activity;