1,3-Cycloaddition of nitrones in ionic liquids catalyzed by Er(III): an easy access to isoxazolidines

Article abstract of DOI:10.1016/j.tetlet.2007.07.219

1,3-Dipolar cycloadditions of nitrones with alkenes afforded the corresponding isoxazolidines in ionic liquids in the presence of Er(OTf)₃. The ionic liquid and the catalyst are recycled up to five times without any specific treatment or loss of activity. Extension of the procedure to the synthesis of isoxazolidinyl nucleosides has been investigated.

Full text of DOI:10.1016/j.tetlet.2007.07.219

Tetrahedron Letters 48 (2007) 7125–7128
1,3-Cycloaddition of nitrones in ionic liquids catalyzed by
Er(III): an easy access to isoxazolidines
Olga Bortolini,* Antonio De Nino, Loredana Maiuolo,* Beatrice Russo,
Giovanni Sindona and Amedeo Tocci
`
Dipartimento di Chimica, Universita della Calabria, Via Bucci 12 C, 87036 Rende (CS), Italy
Received 13 June 2007; revised 27 July 2007; accepted 31 July 2007
Available online 6 August 2007
Abstract—1,3-Dipolar cycloadditions of nitrones with alkenes afforded the corresponding isoxazolidines in ionic liquids in the pres-
ence of Er(OTf)3. The ionic liquid and the catalyst are recycled up to five times without any specific treatment or loss of activity.
Extension of the procedure to the synthesis of isoxazolidinyl nucleosides has been investigated.
Ó 2007 Elsevier Ltd. All rights reserved.
The 1,3-dipolar cycloaddition reactions represent the
favourite method for the construction of five-membered
heterocycles, important frameworks of various natural
products.1 In particular the 1,3-dipolar cycloadditions
of nitrones with alkenes afforded isoxazolidines, which
are interesting intermediates for the synthesis of b-ami-
no alcohols and alkaloids2,3 or, more recently, of cyclic
and bicyclic 4’aza analogues of 20,30-dideoxynucleo-
sides,4 the isoxazolidinyl nucleosides active against
HIV ‘in vitro’ tests.5,6 One of the major drawbacks of
this kind of reactions, however, is the drastic experimen-
tal conditions required to obtain cycloadducts in satis-
factory yields. Lewis acid catalysis has been used to
enhance reaction rates providing, in the same time, a
strict control on regio-, diastero-, and enantioselectiv-
ity.7 In the Lewis acid-catalyzed 1,3-dipolar cycloaddi-
tion the coordination of the Lewis acid to the oxygen
tion since classical organic reactions can be performed
in these media with great advantages (yield and selectiv-
ity) as compared to conventional conditions. Taking
into account the advantages offered by ILs, we have
combined our past experience in the field of cycloaddi-
tions4 and catalysis with the versatile properties of
ILs10 with the aim to find new routes for appealing isox-
azolidine synthesis.
Initially we have focused our attention on the cycloaddi-
tion of the model N-benzyl C-phenyl nitrone 1a with
dipolarophile butyl vinyl ether 2, catalyzed by Er(OTf)3
in bmim(OTf) (1-butyl-3-methyl imidazolium, TfOꢀ ¼
11
CF3SO3ꢀÞ at room temperature.
O
R
H
O
bmim(OTf)
Er(OTf)3
R
O
N
N
+
O
atom of nitrone gives a dominant LUMOnitrone
–
Ph
Ph
HOMOalkene interaction, making this approach more
1a R=CH2Ph
1b R=Me
2
3a
3b
selective.7b
The use of ionic liquids (ILs)8 as support for organic
synthesis, in particular in cycloaddition reactions, has
been described in some recent publications.9 Ionic liq-
uids have received in latest years a good deal of atten-
As shown in Table 1, the presence of the catalyst, its
loading and increasing amounts of the dipolarophile
strongly influence the reaction rates. For a ratio 1a/2/
Er(OTf)3 of 1:20:0.2 an almost complete conversion to
cycloaddition product 3a is observed in reasonable reac-
tion times (3 h), at room temperature (entry 8). A similar
conversion and yield may be obtained employing a low-
er amount of alkene but a higher temperature (entry 6).
Compared to conventional conditions the cycloaddition
reactions performed in ionic liquids are much faster and
Keywords: 1,3-Dipolar cycloadditions; Isoxazolidines; Ionic liquids;
Er(III) catalyst.
*
Corresponding authors. Tel.: +39 0984 492850; fax: +39 0984 493307
(O.B.); tel.: +39 0984 492853 (L.M.); e-mail addresses: o.bortolini@
unical.it; maiuolo@unical.it
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.219

7126
O. Bortolini et al. / Tetrahedron Letters 48 (2007) 7125–7128
Table 1. Reaction of nitrone 1a (1 mmol) with butyl vinyl ether 2, in different experimental conditions
Entry
Alkene 2 (mmol)
Er(OTf)3 (mmol)
T (°C)
Solvent
Time (h)
Conversion, % (Yield, %)
3a endo:exo ratio
1
2
3
4
5
6
7
8
9
20
5
5
—
25
25
25
100
25
100
25
25
25
110
bmim(OTf)
bmim(OTf)
bmim(OTf)
bmim(OTf)
bmim(OTf)
bmim(OTf)
bmim(OTf)
bmim(OTf)
MeOH
2
3
1
1
1
3
1
3
3
3
—
—
b
0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
64 (60)a
64
53:47
54:46
60:40
51:49
63:37
62:38
60:40
65:35
5
15
75
15
15
20
20
20
20
92 (89)
80 (78)
96 (90)
22 (18)
65 (50)
10
Toluene
a Determined by GC analysis with an internal standard.
b Not determined.
Table 2. Reaction of N-benzyl C-phenyl nitrone 1a and N-methyl C-phenyl nitrone 1b with various alkenes catalyzed by Er(OTf)3 in bmim(OTf) at
25 °C
Entry
Nitrone
Alkene
Time (h)
Product R = CH2Ph or CH3
Conversion, % (Yield, %)a
endo:exo ratio
O
3c16
3d17
96 (91)
99
60:40
40:60
R
O
1
2
1a
1b
3
1
O
N
Ph
O
O
R
R
O
N
O
O
3
4
1a
1b
3
3
3e
3f
99 (95)
84
57:43
39:61
Ph
O
O
N
5
6
1a
1b
3
3
3a13a
3b
96 (90)
75
62:38
40:60
Ph
O
O
O
R
R
N
7
8
1a
1b
5
1b
3g18
3h14
70 (65)
99
77:23
37:63
O
O
Ph
N
O
O
9
10
1a
1b
1b
0.5b
3i14
3l14
99 (95)
99
26:74
25:75
Ph
R
O
N
11
12
1a
1b
5b
3
3m
3n
66 (63)
75
36:64
42:58
Ph
O
O
NH
NH
13
1a
48
3o
30c
62:38
O
N
O
R
O
N
Ph
N
a Determined by GC analysis with an internal standard.
b Reaction performed at 0 °C.
c 2.5 mL of IL is used in this case.

O. Bortolini et al. / Tetrahedron Letters 48 (2007) 7125–7128
7127
selective. As an example, the reaction between 1a and 2,
catalyzed by Er(OTf)3 (0.2 mmol) afforded cycloaddi-
tion derivative 3a after 3 h in MeOH in 22% conversion
and 18% yield (entry 9) and in refluxing toluene in 65%
conversion, 50% yield (entry 10), respectively.
Worthy of note the reaction occurs also with vinyl
nucleobases as 1-vinyl thymine to afford the correspond-
ing cycloaddition product 3o, although in moderate
yield, entry 13 of Table 2.15 We have already mentioned
the pharmaceutical importance of these isoxazolidinyl
nucleosides and efforts are currently under way in order
to optimize yields and selectivities of these specific
reactions.
Isolation of the cycloadduct is simple and straightfor-
ward. Work-up consisted in the dilution of reaction mix-
ture with water and extraction of isoxazolidine with
diethyl ether, followed by purification of the product
by flash chromatography and NMR analysis to establish
the endo:exo ratio. Furthermore, water was removed
from the aqueous phase under vacuum and the ionic
liquid, containing the Er(OTf)3, was reused up to five
times without loss of activity nor selectivity; conversion
96%, endo:exo ratio 62:38 after five cycles. We have
intentionally stopped the recycle at the fifth cycle, how-
ever we are convinced that this process may be carried
on many more times.
In conclusion we have shown that 1,3-dipolar cycloaddi-
tions of nitrones with alkenes in the presence of
Er(OTf)3 may be conveniently carried out in ionic liq-
uids at room temperature with the obtainment of the
corresponding isoxazolidines in good conversions and
yields. The ionic liquid and the catalyst may be recycled
several times without loss of activity nor selectivity.
Acknowledgement
To explore the potential of this procedure we have ex-
tended the protocol, optimized as shown in Table 1, to
N-methyl C-phenyl nitrone 1b and to many different al-
kenes, obtaining in all cases the corresponding isoxazoli-
dines in rather good conversions and yields, Table 2.
The reaction of nitrones 1a,b with the vinyl ethers of
Table 2 is highly regioselective, affording exclusively
5-substituted isoxazolidines, in agreement with the liter-
ature reports.7a In a typical procedure 1 mmol of nitrone
was mixed with 0.2 mmol of Er(OTf)3 in bmim(OTf)
1 mL under stirring, at room temperature. After
30 min, 20 mmol of dipolarophile were added and the
progress of the reaction was monitored by GC analysis.
The mixture was then poured into water and extracted
with Et2O to obtain the desired isoxazolidines and to
recover the ionic liquid containing the catalysts, as
described in previous paragraphs.
This work is supported by the University of Calabria.
Supplementary data
Supplementary data (selected spectrometric (EI, APCI–
MS) data of the isoxazolidines) associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2007.07.219.
References and notes
1. Frederickson, M. Tetrahedron 1997, 53, 403–425.
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the resonances of proton Ha.14
3. (a) Seerden, J.-P. G.; Boeren, M. M. M.; Scheeren, H. W.
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OR'
Ha
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Ph
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endo bicyclic isomer (n=2,3)
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As shown in Table 2 the endo:exo selectivity is rather
modest, in agreement with the literature reports that,
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At the moment we have no explanation why the endo:
exo ratio overturns by passing from N-benzyl C-phenyl
nitrone 1a to N-methyl C-phenyl nitrone 1b.
´
´
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7128
O. Bortolini et al. / Tetrahedron Letters 48 (2007) 7125–7128
(d) Conti, D.; Rodriquez, M.; Sega, A.; Taddei, M.
Hd, J = 8.38); 3.68 (dd, 1H, J = 6.21, 9.46); 5.16 (dd, 1H,
Ha, J = 3.06, 6.41); 7.25– 7.50 (m, 5H, Ar); 3f (endo) d (J
Hz) 0.94 (d, 3H, CH3, J = 6.70); 0.96 (d, 3H, CH3,
J = 6.70); 1.90 (m, 1H); 2.40–2.50 (m, 1H, Hb); 2.55–2.65
(m, 1H, Hc); 2.82 (s, 3H, CH3); 3.20 (dd, 1H, J = 6.51,
9.27); 3.59 (dd, 1H, J = 6.90, 9.27); 4.04 (dd, 1H, Hd,
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Hz), 1.41–1.64 (m, 2H, 5-H), 1.75–1.91 (m, 2H, 6-H),
3.33–3.54 (m, 1H, Hb), 3.79–4.05 (m, 5H, CH2Ph, Hd, 7-
H), 5.88–5.95 (m, 1H, Ha), 7.05–7.60 (m, 10H, Ar); (endo)
1.60–1.74 (m, 2H, 5-H), 1.95–2.20 (m, 2H, 6-H), 3.11–3.23
(m, 1H, Hb), 3.62–4.08 (m, 3H, CH2Ph; Hd), 4.10–4.18 (m,
2H, 7-H), 5.90–6.02 (m, 1H, Ha), 7.10–7.52 (m, 10H, Ar);
3n 2-methyl-3-phenyl-1,8-dioxa-2-aza-bicyclo[4.3.0]non-
ane (exo) d (J Hz) 1.52–1.70 (m, 2H, 5-H), 1.72–1.84 (m,
2H, 6-H), 2.71 (s, 3H, CH3), 3.21–3.32 (m, 1H, Hb), 3.76–
3.88 (m, 1H, Hd), 3.98–4.10 (m, 1H, 7-H), 5.74–5.81 (m,
1H, Ha), 7.20–7.41 (m, 5H, Ar); (endo) 1.62–1.74 (m, 2H,
5-H), 1.83–1.98 (m, 2H, 6-H), 2.56 (s, 3H, CH3), 3.16–3.22
(m, 1H, Hb), 3.55–3.89 (m, 3H, Hd, 7-H), 5.87–5.94 (m,
1H, Ha), 7.25–7.50 (m, 5H, Ar).
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CH3, J = 7.2); 1.33–1.44 (m, 2H); 1.48–1.58 (m, 2H); 2.33–
2.43 (m, 1H, Hb); 2.61 (s, 3H, CH3); 2.84–2.94 (m, 1H,
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(dd, 1H, J = 6.85, 9.30); 4.00 (dd, 1H, Hd, J = 6.17, 9.84);
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J = 6.61); 0.91 (d, 3H, CH3, J = 6.61); 1.87 (m, 1H); 2.24–
2.38 (m,1H, Hb); 2.82–2.94 (m, 1H, Hc); 3.15 (dd, 1H,
J = 6.76, 9.31); 3.46 (dd, 1H, J = 6.76, 9.31); 3.62–3.74 (m,
2H); 4.15 (d, 1H, J = 14.57); 5.12 (dd, 1H, Ha, J= 2.70,
6.31); 7.15–7.52 (m, 10H, Ar); 3e (endo) d (J Hz) 0.96 (d,
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1H); 2.40–2.51 (m, 1H, Hb); 2.58–2.68 (m, 1H, Hc); 3.18
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(s, 2H); 4.21 (dd, 1H, Hd, J = 6.30, 10.36); 5.17 (d, 1H, Ha,
J = 4.80); 7.18–7.51 (m, 10H, Ar); 3f (exo) d (J Hz) 0.94
(d, 3H, CH3, J = 6.70); 0.95 (d, 3H, CH3, J = 6.70); 1.96
(m, 1H); 2.31–2.41 (m, 1H, Hb); 2.58 (s, 3H, CH3); 2.85–
2.95 (m,1H, Hc); 3.17 (dd, 1H, J = 7.39, 9.46); 3.43 (t, 1H,
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