New phenylselanyl group activation: Synthesis of aziridines and oxazolidin-2-ones

Article abstract of DOI:10.1039/b406566m

After the study of different phenylselanyl group activators, halogenation by N-bromosuccinimide (NBS) has been shown to be the most suitable manner for cyclizing β-phenylselanyl amines into aziridines and also enabled production of oxazolidin-2-ones from N-Boc β-phenylselanyl amines in excellent yield.

Full text of DOI:10.1039/b406566m

View Article Online / Journal Homepage / Table of Contents for this issue
New phenylselanyl group activation: synthesis of aziridines and
oxazolidin-2-ones†
Catherine Miniejew, Francis Outurquin* and Xavier Pannecoucke
Université et INSA de ROUEN, IRCOF, UMR CNRS6014, 1 rue Tesnière,
76131 Mont Saint-Aignan, France.
E-mail: francis.outurquin@univ-rouen.fr; Fax: (33) 2.35.52.29.59; Tel: (33) 2.35.52.24.27
Received 30th April 2004, Accepted 30th April 2004
First published as an Advance Article on the web 11th May 2004
Table 1 Cyclization of 2a induced by different phenylselanyl group
activations
After the study of different phenylselanyl group activators,
halogenation by N-bromosuccinimide (NBS) has been
shown to be the most suitable manner for cyclizing
ꢀ-phenylselanyl amines into aziridines and also enabled
production of oxazolidin-2-ones from N-Boc ꢀ-phenyl-
selanyl amines in excellent yield.
Entry
Activation
Yield (%)
The conceptually simple approach of heterocycles probably
relies on the cyclization of appropriate heterosubstituted
precursors bearing internal leaving groups. One such group
could be a selanyl group which is easily displaced under mild
experimental conditions by several nucleophiles when it is
activated in oxidation state  as selenone or selenonium
salt.1 The synthesis of epoxides promoted by alkylation of
β-phenylselanyl alcohols has been reported in the literature.2
More recently, aziridines have been prepared by the oxidation
of N-protected β-phenylselanyl amines.3 However, a selenoxide
syn-elimination sometimes occurs as a competing pathway. In
our group, the diastereoselective preparation of β-phenylselanyl
amines and their conversion into aziridines, promoted by
methylation with the Meerwein salt, has been investigated
(Scheme 1).4
1
2
3
4
5
6
7
8
MeO3BF4, 20 ЊC, 12 h
mCPBA, Ϫ78 ЊC, 20 min
H2O2, 20 ЊC, 30 min
PhSeCl, 20 ЊC, 5 min
PhSeBr, 20 ЊC, 5 min
SO2Cl2, 20 ЊC, 5 min
Br2, 20 ЊC, 5 min
58
32
25
64
70
63
75
80
NBS, 20 ЊC, 5 min
Table 2 Cyclization of 2b induced by different phenylselanyl group
activations
Entry
Activation
Product (yield, %)
1
2
3
MeO3BF4, 20 ЊC, 12 h
mCPBA, Ϫ78 ЊC, 20 min
NBS, 20 ЊC, 5 min
4b (50), 3b (21)
5b (56), 6b (24)
3b (58)
Scheme 1 Reagents and conditions: i. NH2Bn, MgSO4; CH2Cl2, 20 ЊC,
4 h; ii. NH2Bn, TiCl4, Et2O, 20 ЊC, 4 h; iii. NaBH3CN, AcOH, EtOH,
Ϫ78 ЊC, 1 h; iv. Me3OBF4, CH2Cl2, 20 ЊC, 12 h.
The superiority of this new activation method became even
clearer with the more hindered β-phenylselanyl amine 2b.
Promoting the reaction with the Meerwein salt afforded the
N-methylated β-phenylselanyl amine 4b as the major product
and the aziridine 3b in only 21% yield (Table 2; entry 1).
Suprisingly, mCPBA converted the substrate 2b into the
α-phenylselanyl imine 5b and a small amount of selenoxide
syn-elimination product 6b (Table 2; entry 2). Whereas using
NBS, the aziridine 3b was the sole product obtained in 58%
yield (Table 2; entry 3).
Nevertheless with bulky R1 groups, side reactions and
formation of N-methylated products were observed. Herein, we
report a new method to trigger the cyclization of selenenylated
substrates while limiting the side reactions.
During the course of our work on the reactivity of
β-phenylselanyl amines, we undertook a comparative study
of the different methods promoting their cyclization into
aziridines (Table 1). Treatment of the β-phenylselanyl amine 2a
with the Meerwein salt, afforded the aziridine 3a in 58% yield
(Table 1; entry 1). Resorting to an oxidant like mCPBA or
hydrogen peroxide led to 3a together with by-products derived
from selenoxide syn-elimination (Table 1; entries 2,3). However,
the cyclisation yield increased when the reaction was promoted
by selenenylation (Table 1; entries 4,5). We also decided to try
halogen activators. SO2Cl2 and Br2 gave good yields, 63 and
75% respectively, but the best result was obtained using NBS as
phenylselanyl group activator (80% yield, Table 1; entry 8). In
addition, the conversion of the β-phenylselanyl amine 2a
became very rapid (5 min).
This aziridine synthesis promoted by halogenation was
successfully extended to the β-phenylselanyl amines 2d–h
(Table 3).5 With this versatile method, the aziridines 3d–h were
obtained in 56–80% yield. Nevertheless starting from the
substrate 2c, the desired aziridine 3c was obtained as a mixture
with the β-bromo amine 7c. An unexpected isomerisation was
also observed during the cyclization of compound 2h. Starting
from a single syn diastereomer, the corresponding aziridine 3h
was obtained as a mixture of cis : trans diastereomers (15 : 85).
The stereochemistry of the aziridines were unambigously
assigned by 1H NMR based on the characteristic JH H
2
3
coupling constant.6 It is assumed that intramolecular substi-
tutions usually occur with inversion of configuration. In our
case, the unexpected trans diastereomer may result from an
† Electronic Supplementary Information (ESI) available: experimental
section. See http://www.rsc.org/suppdata/ob/b4/b406566m/
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 7 5 – 1 5 7 6
1575

View Article Online
Table 3 Synthesis of aziridines 3 induced by phenylselanyl group halogenation with NBS
Substrates (syn : anti)4
R1
R2
R3
Products (cis : trans)
Yield (%)
2c
nBu
Me
H
H
Me
Me
H
H
Ph
Me
Et
Ph
H
Ph
H
H
H
H
3c (7c)
36 (32)
56
71
60
65
2d
3d
2e
2f
3f
3e
2g (80 : 20)
2h (100 : 0)
3g (80 : 20)
3h (15 : 85)
80
Table 4 Synthesis of oxazolidin-2-ones 9 induced by phenylselanyl
group halogenation with NBS
It gives access to a wide variety of aziridines, some of which
could not be obtained by previous routes. The developed
activation method also transforms stereospecifically selenenyl-
ated carbamates 8 into oxazolidin-2-ones in excellent yield.
Notes and references
1 C. Paulmier, Inter and Intramolecular Nucleophilic Substitutions of
Activated Phenylselanyl Groups, Phosphorus, Sulfur, Silicon Relat.
Elem., 2001, 172, 25.
2 S. Halazy and A. Krief, Tetrahedron Lett., 1980, 21, 1997;
J. L. Laboureur, W. Dumont and A. Krief, Tetrahedron Lett., 1984,
25, 4569; A. Krief, W. Dumont, D. Van Ende, S. Halazy, D. Labar
and J. L. Laboureur, Heterocycles, 1989, 28, 1203.
3 M. Demarcus, S. N. Filigheddu, A. Mann and M. Taddei, Tetra-
hedron Lett., 1999, 40, 4417; V. R. Ward, M. A. Cooper and
D. Ward, J. Chem. Soc., Perkin Trans. 1, 2001, 944.
Substrates
(syn : anti)
Products
(cis : trans)
R1
R2
Yield (%)
4 S. Boivin, F. Outurquin and C. Paulmier, Tetrahedron Lett., 2000,
41, 663.
8f
Me
Me
Me
H
Et
Ph
9f
87
91
85
8g (80/20)
8h (100/0)
9g (80 : 20)
5 Typical procedure: To the β-phenylselanyl amine (1 mmol) in
acetonitrile (15 ml) was added NBS (195 mg, 1.1 mmol) at room
temperature. After 5 min of stirring the mixture became red–brown
and sodium bicarbonate (212 mg, 2 mmol) was introduced. The
mixture turned rapidly yellow. Water (15 ml) was added and the
aqueous phase was extracted with CH2Cl2 (2 × 15 ml). The com-
bined organic phases were dried with MgSO4 and concentrated.
The crude product was purified by column chromatography (cyclo-
hexane : Et2O, 8 : 2) to afford the desired aziridine.
6 J.-L. Pierre, P. Baret and P. Arnaud, Bull. Soc. Chim. Fr., 1971, 3619.
7 (a) F. Gerhart, W. Higgins, C. Tardif and J. Ducep, J. Med. Chem.,
1990, 33, 2157; M. Kasai and M. Kono, Synlett, 1992, 778;
W. McCoull and F. A. Davis, Synthesis, 2000, 1347; (b) D. J. Ager,
J. Prakash and D. R. Schaad, Chem. Rev., 1996, 96, 835; M. J. Genin,
D. K. Hutchinson, D. A. Allwine, J. B. Hester, D. E. Emmert,
S. A. Garmon, C. W. Ford, G. E. Zurenko, J. C. Hamel,
R. D. Schaadt, D. Stapert, B. H. Yagi, J. M. Friis, E. M. Shobe and
W. J. Adams, J. Med. Chem., 1998, 41, 5144.
8 S. Kano, T. Yokomatsu, H. Iwasawa and S. Shibuya, Tetrahedron
Lett., 1987, 28, 6331; M. Sakaitani and Y. Ohfune, J. Am. Chem.
Soc., 1990, 112, 1150; M. A. Lago, J. Samanen and J. D. Elliot,
J. Org. Chem., 1992, 57, 3493; C. Agami, F. Couty, L. Hamon and
O. Venier, Bull. Soc. Chim. Fr., 1995, 132, 808; F. L. Van Delft,
C. M. Timmers, G. A. Van der Marel and J. H. Van Boom,
Synthesis, 1996, 450; H. Zhao and A. Thurkauf, Synlett, 1999, 1280;
F. Benedetti and S. Norbedo, Tetrahedron Lett., 2000, 41, 10071.
9 M. Tiecco, L. Testaferri, F. Marini, A. Temperini, L. Bagnoli and
C. Santi, Synth. Commun., 1997, 27, 4131.
10 M.-N. Dufour, P. Jouin, J. Poncet, A. Pantaloni and B. Castro,
J. Chem. Soc., Perkin Trans. 1, 1986, 1895; J. Schwerdtfeger,
S. Kolczewski, B. Weber, R. Fröhlich and D. Hoppe, Synthesis, 1999,
1573.
9h (100 : 0)a
a Confirmed by NOE experiment.
intermolecular substitution by a bromide anion prior to the
ring closure.
We next attempted to extend the halogenation promoted
cyclization to oxygenated nucleophiles. Like aziridines,7a
oxazolidin-2-ones7b are attractive targets due to their occurence
in biologically active compounds, synthetic intermediates or
chiral auxiliaries. One method of preparing oxazolidin-2-ones
consists of an intramolecular nucleophilic substitution of carb-
amates bearing an internal leaving group.8 In the literature, the
cyclization of selenenylated carbamates by phenylselanyl
sulfate has been evoked by Tiecco et al. to rationalize the one-
pot transformation of alkenes into 4-substituted oxazolidin-2-
ones.9 We decided to adopt a comparable strategy. Thus, a Boc
protection of compounds 2f–h led to new cyclization substrates
8f–h which reacted with NBS to afford oxazolidin-2-ones 9f–h
in 85–91% yield (Table 4). The stereochemistry of the products
9f–h has been assigned in accordance to the literature data.10
Only an intramolecular SN2 reaction with inversion of con-
figuration at the carbon bearing the selenium group were
observed.
In conclusion, resorting to NBS as an activator of the
phenylselanyl group constitutes a very simple and rapid new
method for cyclizing β-phenylselanyl amines 2 into aziridines 3.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 5 7 5 – 1 5 7 6
1576