Ring opening of unprotected aziridines by zinc selenolates in a biphasic system

Article abstract of DOI:10.1016/j.tetlet.2009.02.156

A set of chiral β-seleno amines were prepared by the ring-opening reaction of unprotected aziridines. Under acid conditions diaryl or dialkyl diselenides were reduced by zinc and treated with unprotected aziridines to produce the desired products in good

Full text of DOI:10.1016/j.tetlet.2009.02.156

Tetrahedron Letters 50 (2009) 2309–2311
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Ring opening of unprotected aziridines by zinc selenolates in a biphasic system
a
a
a
a
Antonio L. Braga a,b, , Ricardo S. Schwab , Eduardo E. Alberto , Syed M. Salman , Josimar Vargas ,
*
Juliano B. Azeredo b
a Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
b Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A set of chiral b-seleno amines were prepared by the ring-opening reaction of unprotected aziridines.
Under acid conditions diaryl or dialkyl diselenides were reduced by zinc and treated with unprotected
aziridines to produce the desired products in good yields. Chiral b-telluro amine was also obtained using
this method.
Received 27 January 2009
Revised 17 February 2009
Accepted 19 February 2009
Available online 25 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
In the past decades, selenium-based methods have developed
rapidly and become a useful tool in the hands of organic chemists.1
Organoselenium compounds have found such wide utility because
of their effects on an extraordinary number of very different reac-
tions, including many carbon–carbon bond formations, under rela-
tively mild reaction conditions.2
Moreover, chiral selenide- and diselenide containing ligands of-
fer attractive and practical options in the development of asym-
metric transformations. They have been employed as useful
catalysts in enantioselective addition of diethylzinc to aldehydes,
conjugate addition of Grignard reagents to enones, and palla-
dium-catalyzed asymmetric allylic substitution.3 However, the
development of new methods for the introduction of selenium-
containing groups into organic molecules, particularly in a ste-
reo-controlled manner, remains a significant challenge.4
On the other hand, chiral aziridines are one of the most versatile
three-membered ring systems in modern synthetic chemistry.
They make up a versatile and useful class of nitrogen-containing
compounds in organic transformations.5 They are also key inter-
mediates for the stereo-controlled synthesis of nitrogen containing
compounds (e.g., amino acids, heterocycles, and peptides).6
In this context, we recently reported the straightforward syn-
thesis of a new set of chiral b-seleno amines through a stereo-
selective aziridine ring opening with selenium nucleophiles, gener-
ated by reducing agents such as NaBH4, LiBHEt3, or indium salts.7
These compounds were successfully applied as ligands in asym-
metric reactions or in the synthesis of selenocysteine derivatives.
Despite such progress, it was not possible to promote the ring-
opening reaction of unprotected aziridines leading to a tedious
and expensive protection–deprotection process.
lides or epoxides.8 We reasoned that this methodology would be
a convenient way to approach the troublesome ring-opening reac-
tion of unprotected aziridines.
Therefore, in connection with our interest in the synthesis and
evaluation of [N, Se]-compounds as chiral ligands in asymmetric
transformations9 and in biological screenings,10 herein we report
a simple and efficient synthesis of b-seleno amines. These com-
pounds were easily prepared by reaction of unprotected aziridines
and diaryl or dialkyl diselenides. We employed an acid biphasic
system and an inexpensive and commercially available zinc dust
as reducing agent.
In order to evaluate the performance of the aziridine ring-open-
ing reaction, we firstly used diphenyl diselenide and aziridines de-
rived from L-phenylalanine as standard reagents. Unprotected
aziridine 1a,11 as well as Ts and Boc-protected aziridines,12 1b
and 1c, respectively, was tested using Zn as reducing agent in an
HCl/diethyl ether biphasic system, as illustrated in Scheme 1.
A good result was obtained for unprotected aziridine 1a, afford-
ing the desired b-seleno amine 2a in 77% yield. The reaction was
regioselective, giving the product through the attack of selenolate
to the less hindered aziridine carbon. The protected aziridine 1b
(Ts) gave the product in 33% yield, and no product was observed
for aziridine 1c (Boc).
Encouraged by this result, we tested various reaction conditions
in an attempt to improve the efficiency of the ring opening of
PhSe)2, Zn0
Ph
Ph
SePh
HCl / Et2O
N
NHR
Recently, Santi et al. described a zinc-mediated preparation of
selenols and ‘in situ’ reaction with electrophiles, such as alkyl ha-
R
1a: R = H
1b: R = Ts
1c: R = Boc
2a: R = H, 77%
2b: R = Ts, 33%
2c: R = Boc, no reaction
* Corresponding author. Tel.: +55 55 3220 8761; fax: +55 55 3220 8998.
E-mail address: albraga@quimica.ufsm.br (A.L. Braga).
Scheme 1. Ring opening of protected and unprotected aziridines 1a–c.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.156

2310
A. L. Braga et al. / Tetrahedron Letters 50 (2009) 2309–2311
Table 1
Table 2
Optimization of the ring-opening reaction of unprotected aziridines by diphenyl
diselenide
RYYR / Zn0
HCl / Et2O
Ph
Ph
YR
N
PhSe)2, Zn0
NH2
R
R
H
SePh
2 d-p
HCl / Solvent
N
H
1a
NH2
Yielda (%)
2
1
Entry
R
Y
Product
1
2
3
4
5
6
7
8
9
2-MeC6H4
4-MeC6H4
2-ClC6H4
4-ClC6H4
4-FC6H4
2-OMeC6H4
4-OMeC6H4
2-Pyridyl
Bn
Se
Se
Se
Se
Se
Se
Se
Se
Se
Se
Se
Te
2d
2e
2f
2g
2h
2i
2j
2k
2l
35
60
55
80
83
51
58
46
35
35
52
40
Entrya
R
Solvent
Temp (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
i-Pr
i-Bu
Et2O
THF
rt
rt
rt
rt
rt
rt
rt
Reflux
Reflux
rt
77
64
26
75
60
52
53
60
43
58
70
Hexane
AcOEt
CH2Cl2
EtOH
H2O
Et2O
AcOEt
Et2O
10
11
12
n-Bu
Et
Ph
2m
2n
2o
10
11
Et2O
rt
a
Isolated yields.
a
Reagents and conditions: Et2O (4 mL), HCl (10%, 4 mL), PhSeSePh (0.25 mmol),
and zinc dust (7.7 mmol). 10–30 min after addition of unprotected aziridine
(0.5 mmol).
b
Isolated yields.
R'SeSeR'
Zn
unprotected aziridines (Table 1). We chose PhSeSePh as standard
diselenide, and to check the best solvent and temperature for this
system we selected aziridine 1a as substrate (entries 1–9).
R
R
R
Solvent
HCl
R'SeZnSeR'
SeR'
N
H
N
H
NH2
The complete conversion of diselenide into the corresponding
selenolate by the addition of zinc under acid conditions was dem-
onstrated by discoloration of the mixture which was followed by
the addition of aziridine. It was found that the solvent had a strong
influence on the formation of the product, while ethereal solvents
such as Et2O and THF, showed better results (entries 1 and 2). Apo-
lar hexane (entry 3) did not afford the b-seleno amine 2 in an
appreciable yield. The use of CH2Cl2 allowed the formation of prod-
uct 2 in 60% yield (entry 5). A good result was also achieved by
using ethyl acetate, giving the product in a yield close to that
achieved with Et2O (entry 4). In an attempt to make the reaction
more environmentally friendly, we employed solvents such EtOH
and water (entries 6 and 7), but unfortunately the product was ob-
tained only in moderate yield. In addition, the reaction was carried
out in Et2O and AcOEt under reflux in an effort to increase the yield,
but quite disappointing results were observed (entries 8 and 9).
When the reaction was performed with aziridines derived from
Cl
H
2
1
Scheme 2. Proposed mechanism for zinc-mediated ring opening of unprotected
aziridines by diselenides.
goal in organochalcogen chemistry, due to difficulties in its prepa-
ration and handling.9g,h
We believe that the reaction occurs firstly through the ‘in situ’
formation of water-soluble zinc selenolate. The activation of the
unprotected aziridine leads to the protonated intermediate, which
undergoes the ring opening by zinc selenolate in the aqueous layer,
as depicted in Scheme 2. We conjecture that the protonation of the
aziridines is the most crucial step, activating them to undergo the
ring-opening reaction by zinc selenolates. An important feature of
the present method is its regioselectivity, as the product is given
exclusively through the attack of selenolate to the less-hindered
aziridine carbon. Moreover, HPLC analysis of the b-seleno amines
2 and authentic samples showed the retention of the configuration
of the chiral center, demonstrating that there was no racemization
of the incoming product.7a
In summary, we presented in this report a simple and efficient
approach for the preparation of chiral b-seleno amines. The desired
products were prepared in a biphasic system, employing inexpen-
sive and commercially available zinc dust, unprotected aziridines,
and alkyl or aryl diselenides. A notable feature of our approach is
the regioselectivity of the ring-opening reactions of unprotected
aziridines, leading to the desired products in good yields, which
avoids expensive protection-deprotection chemistry. A broad set
of chiral b-seleno amines was synthesized, as well as a b-telluride
amine analogue.
L
-valine and
the products were obtained in good yields, but slightly lower than
those found for aziridine 1a derived from -phenylalanine.
L-leucine (entries 10 and 11) using the best conditions,
L
Based on these results and in order to widen the scope of our
protocol, we then tested a broader range of diselenides.13 The re-
sults are listed in Table 2. Notably, electron-withdrawing groups
showed better results compared to electron-donating ones. In the
reaction using 4-ClC6H4Se)2 and 4-FC6H4Se)2 the yields were 80%
and 83%, respectively (entries 4 and 5), which were quite higher
than the results for 4-MeC6H4Se)2 and 4-MeOC6H4Se)2 (60% and
58%; entries 2 and 7). Another feature of this system is the strong
influence of hindrance effects in the diselenide moiety. When
ortho-substituted diselenides were applied, there was a dramatic
decrease in yields both for electron-donating and -withdrawing
groups (entries 1, 3, and 6 vs 2, 4, and 7). Dibenzyl diselenide
and 2-pyridine diselenide were also tested (entries 8 and 9). The
b-seleno amines 2m and 2n, with aliphatic moieties attached to
selenium were also obtained by using dibutyl diselenide and
diethyl diselenide (entries 10 and 11). To further improve our
method, we promoted the reaction using diphenyl ditelluride.
Although the yield was 40% (entry 12) our approach is a promising
strategy for the preparation of b-telluro amine, which is a current
Acknowledgments
The authors thank CNPq, Capes, INCT-Catálise, and FAPERGS for
financial support. S.M.S. thanks TWAS-CNPq for the PhD
fellowship.

A. L. Braga et al. / Tetrahedron Letters 50 (2009) 2309–2311
2311
9. For selected examples see: (a) Braga, A. L.; Silva, S. J. N.; Lüdtke, D. S.; Drekener,
R. L.; Silveira, C. C.; Rocha, J. B. T.; Wessjohann, L. A. Tetrahedron Lett. 2002, 43,
7329; (b) Braga, A. L.; Milani, P.; Paixão, M. W.; Zeni, G.; Rodrigues, O. E. D.;
Alves, E. F. Chem. Commun. 2004, 2488; (c) Schneider, P. H.; Schrekker, H. S.;
Silveira, C. C.; Wessjohann, L. A.; Braga, A. L. Eur. J. Org. Chem. 2004, 2715; (d)
Braga, A. L.; Paixão, M. W.; Milani, P.; Silveira, C. C.; Rodrigues, O. E. D.; Alves, E.
F. Synlett 2004, 1297; (e) Braga, A. L.; Lüdtke, D. S.; Vargas, F.; Paixão, M. W.
Chem. Commun. 2005, 2512; (f) Braga, A. L.; Lüdtke, D. S.; Alberto, E. E.; Sehnem,
J. A. Tetrahedron 2005, 61, 11664; (g) Braga, A. L.; Sehnem, J. A.; Vargas, F.;
Braga, R. C. J. Org. Chem. 2005, 70, 9021; (h) Braga, A. L.; Vargas, F.; Galetto, F. Z.;
Paixão, M. W.; Schwab, R. S.; Taube, P. T. Eur. J. Org. Chem. 2007, 5327; (i)
Schwab, R. S.; Galetto, F. Z.; Azeredo, J. B.; Braga, A. L.; Lüdtke, D. S.; Paixão, M.
W. Tetrahedron Lett. 2008, 49, 5094.
10. Selected examples: (a) Farina, M.; Barbosa, N. B. V.; Nogueira, C. W.; Folmer, V.;
Zeni, G.; Andrade, L. H.; Braga, A. L.; Rocha, J. B. T. Braz. J. Med. Biol. Res. 2002, 35,
636; (b) Burger, M.; Fachinetto, R.; Calegari, L.; Paixão, M. W.; Braga, A. L.;
Rocha, J. B. T. Brain Res. Bull. 2004, 64, 339; (c) Rosa, R. M.; de Oliveira, R. B.;
Saffi, J.; Braga, A. L.; Roesler, R.; Pizzol, F. D.; Moreira, J. C. F.; Brendel, M.;
Henriques, J. A. P. Life Sci. 2005, 77, 2398; (d) Centurião, F. B.; Corte, C. L. D.;
Paixão, M. W.; Braga, A. L.; Zeni, G.; Emanuelli, T.; Rocha, J. B. T. Brain Res. 2005,
1039, 146; (e) Soares, F. A.; Farina, M.; Böettcher, A. C.; Braga, A. L.; Rocha, J. B.
T. Environ. Res. 2005, 98, 46; (f) de Avila, D. S.; Beque, M. C.; Folmer, V.; Braga, A.
L.; Zeni, G.; Nogueira, C. W.; Soares, F. A. A.; Rocha, J. B. T. Toxicology 2006, 224,
100; (g) Braga, A. L.; Alberto, E. E.; Soares, L. C.; Rocha, J. B. T.; Sudati, J. H.; Ross,
D. H. Org. Biomol. Chem. 2009, 7, 43.
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13. General procedure: In a 25 mL round-bottomed flask, under argon atmosphere,
was prepared the biphasic solution by the addition of Et2O (4 mL) and HCl
(10%, 4 mL), to this solution were added firstly the diaryl or dialkyl diselenide
(0.25 mmol) and zinc dust (500 mg, 7.7 mmol). The mixture was allowed to stir
until the yellow solution became colourless (10–30 min), then the unprotected
aziridine (0.5 mmol) was added and the reaction was stirred at room
temperature for 24 h. After completion of the reaction, as indicated by TLC,
the reaction mixture was treated with saturated aqueous ammonium chloride
solution and the whole mixture was extracted 3 times with CH2Cl2 and the
combined organic fractions were collected, dried over MgSO4, filtered and the
solvent was then removed in vacuo. The crude mixture was purified by column
chromatography on silica gel eluting with hexane–ethyl acetate (9:1) and after
with ethyl acetate.
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8. Santi, C.; Santoro, S.; Testaferri, L.; Tiecco, M. Synlett 2008, 1471.