1,3-Cycloaddition of nitrile oxides in ionic liquids. An easier route to 3-carboxy isoxazolines, potential constrained glutamic acid analogues

Article abstract of DOI:10.1016/S0040-4039(03)01195-X

Several improvements in the cycloaddition of carboethoxyformonitrile oxide (CEFNO) with different alkenes are observed in the ionic liquids [bmim][BF₄] and [bmim][PF₆]. The possibility of obtaining good yields of the corresponding is

Full text of DOI:10.1016/S0040-4039(03)01195-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5327–5330
1,3-Cycloaddition of nitrile oxides in ionic liquids. An easier
route to 3-carboxy isoxazolines, potential constrained glutamic
acid analogues
Dario Conti, Manuela Rodriquez, Alessandro Sega* and Maurizio Taddei
Dipartimento Farmaco Chimico Tecnologico, Universita` degli Studi di Siena, Via A. Moro, 53100 Siena, Italy
Received 23 April 2003; revised 9 May 2003; accepted 9 May 2003
Abstract—Several improvements in the cycloaddition of carboethoxyformonitrile oxide (CEFNO) with different alkenes are
observed in the ionic liquids [bmim][BF4] and [bmim][PF6]. The possibility of obtaining good yields of the corresponding
isoxazolines opens the way towards parallel collections of glutamic acid (Glu) analogues. © 2003 Elsevier Science Ltd. All rights
reserved.
Glutamic acid is a central excitatory neurotransmitter
acting through two heterogeneous families of mem-
brane associated receptors. Their activation produces a
large spectrum of physiological functions in the healthy
and in the diseased central nervous system (CNS).1
These receptors, including all the recently discovered
subtypes, are potential therapeutic targets. Conse-
quently the design and the synthesis of new ligands are
of great interest in the CNS drug discovery process.2
approach to dicarboxy-isoxazolines that provides an
acceptable level of molecular diversity. Consequently,
we decided to investigate this reaction in order to let it
amenable for the preparation of arrays of molecules in
a parallel way. Most of the reported procedures3b,5
generated CEFNO in situ by base treatment of the
ethyl chlorooximidoacetate derived from glycine6 as
originally described by Kozikowski.7
Following that report, ethyl glycine was transformed in
good yields into compound 2 and this product, after
purification by crystallization, was dissolved in diethyl
ether together with ethyl acrylate and to this mixture a
base (Et3N) was slowly added to generate CEFNO for
the immediate cycloaddition. In our hands, this route
produced the required product 3 in low yields (20–30%)
together with larger amounts of furoxane 4. As
reported in the original paper and further confirmed by
the experience of other authors, the addition of the base
with a syringe pump and the use of large amounts of
the dipolarophile increased the yields of 3 to 45%.
Isoxazoles and isoxazolines have found several impor-
tant applications as lead structures for new Glu ligand
design.3 Following our interest in developing new
strategies for the generation of molecular diversity,4we
became interested in the preparation of small libraries
of 3-carboxy 1,2-isoxazolines, one of the most simple
structures resembling Glu in a constrained form
(Scheme 1).
Cycloaddition of carboethoxyformonitrile oxide
(CEFNO) with acrylates is the most straightforward
Scheme 1.
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01195-X

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D. Conti et al. / Tetrahedron Letters 44 (2003) 5327–5330
When the same protocol was applied to other dipolar-
ophiles (as diethyl malonate or acrylonitrile) we always
obtained low yields of the corresponding isoxazolines
contaminated by furoxane 4 (Scheme 2).
and we were pleased to observe that isoxazoline 3 was
formed rapidly and in high yield. Moreover, the
amount of furoxane formed was largely reduced. To
explore the potential and the limits of this new proce-
dure of cycloaddition, we repeated the protocol using
different alkenes obtaining always isoxazolines 5–15 in
good yields without the need of chromatographic
separation.
As these conditions are unsuitable for the development
of a parallel synthesis, we started to investigate differ-
ent conditions. Furoxane 4 was formed by dimerization
of unstable CEFNO that did not conclude the cycload-
dition with the acrylate and this is the reason why a
slow addition with a syringe pump is required in order
to get good yields of the cycloadduct. In order to verify
if a more polar environment could stabilize CEFNO,
we tried the reaction in an ionic liquid8 ([bmim][BF4])
In a typical procedure 0.65 mmol of alkene were mixed
with KHCO3 (0.65 mmol) in [bmim][BF4] (0.2 g), solid
CEFNO (0.65 mmol) was added and the mixture stirred
at room temperature for 5–12 h. When the starting
materials were disappeared, the mixture was treated
Scheme 2.
Scheme 3.

D. Conti et al. / Tetrahedron Letters 44 (2003) 5327–5330
5329
Scheme 4.
Acknowledgements
with an organic solvent immiscible with the ionic liquid
(diethyl ether, THF or EtOAc) that selectively extracted
the isoxazolines. The organic solvent was evaporated
and the products isolated in the yields reported in
Scheme 3 and with purities ranging from 80 to 95% (1H
NMR analysis, 200 MHz). Analytical samples were
further purified by column chromatography.
This work was in part supported by MIUR (Rome)
within the project PRIN 2001. Nikem Research (Milan)
is also acknowledged for financial support.
References
In any case investigated, we observed exclusively the
formation of the 5-substituted isoxazolines as suggested
by the low field values of the CH signal located around
l 4.0–5.0.9
1. Bra¨uner-Osborne, H.; Egebjerg, J.; Nielsen, E. Ø.; Mad-
sen, U.; Krogsgaard-Larsen, P. J. Med. Chem. 2000, 43,
2609.
2. Parsons, C. G.; Danysz, W.; Quack, G. Drug News
Perspect. 1998, 11, 523.
As reported in Scheme 3, the reaction gave good yields
(as expected) with electron-rich alkenes and even conju-
gated dipolarophiles were successfully transformed into
the corresponding isoxazolines, expanding the poten-
tials of this reaction.10 To our knowledge, this is the
first example of the improvement in the cycloaddition
of nitrile oxides using ionic liquids.11 The only limita-
tion concerns the reaction with benzyl crotonate that
gave product 15. Probably the presence of the ionic
liquid in basic medium induced the thermodynamically
unfavorable migration of the double bond to the termi-
nal position, generating a more reactive alkene that
immediately gave rise to the cycloaddition.
3. (a) Kromann, H.; Slok, F. A.; Stensbol, T. B.; Bra¨uner-
Osborne, H.; Madsen, U.; Krogsgaard-Larsen, P. J. Med.
Chem. 2002, 45, 988; (b) Conti, P.; De Amici, M.; Roda,
G.; Vistoli, G.; Stensbol, T. B.; Bra¨uner-Osborne, H.;
Madsen, U.; Toma, L.; De Micheli, C. Tetrahedron 2003,
59, 1443 and references cited therein.
4. Giacomelli, G.; Porcheddu, A.; Salaris, M.; Taddei, M.
Eur. J. Org. Chem. 2003, 537.
5. (a) Kusumi, T.; Kakisawa, H.; Suzuki, S.; Harada, K.;
Kashima, C. Bull. Chem. Soc. Jpn. 1978, 51, 1261; (b)
Abbot, S. D.; Lane-Bell, P.; Sidhu, K. P. S.; Vederas, J.
C. J. Am. Chem. Soc. 1994, 116, 6513; (c) Da Ros, T.;
Prato, M.; Lucchini J. Org. Chem. 2000, 65, 4289; (d)
Chen, Y.; Zhang, W.; Chen, X.; Wang, J.; Wang, P. G. J.
Chem. Soc., Perkin Trans. 1 2001, 1716.
6. For alternative approaches to this kind of nitrile oxide,
see: Maiti, D.; Bhattacharya, P. K. Synlett 1998, 385;
Kiegiel, J.; Poplawska, M.; Jo´zwik, J.; Kosior, M.;
Jurezak, J. Tetrahedron Lett. 1999, 40, 5605; Matt, C.;
Gissot, A.; Wagner, A.; Mioskowski, C. Tetrahedron
Lett. 2000, 41, 1191.
Compounds 3 and 6 were transformed into the corre-
sponding acids 16 and 17 whereas, from compound 5,
an array of derivatives may be prepared. Compound 18
in Scheme 4 was synthesized, as an example for the
preparation of arrays of isoxazoline carboxamides, by
deprotection of the carboxyl group in position 5, (H2
Pd/C in CHCl3, 96% yield) coupling with an amine
EDC, DMAP, CH2Cl2, 89% yield) followed by amida-
tion of the ethyl ester in position 3 carried out in the
presence of Me3Al.
7. Kozikowski, A. P.; Adamczyk, M. J. Org. Chem. 1983,
48, 366.
8. [bmim][BF4] and [bmim][PF6]: butyl metylimidazolium
terafluoborate and hexafluorophosphate were prepared
following: Dupont, J.; Consorti, C.; Suarez, P. A. Z.; de
Souza, R. F. Org. Synth 2002, 79, 236. For a recent
review on the applications of ionic liquids in organic
synthesis, see: Zhao, H.; Malhotra, S. V. Aldrichim. Acta
2002, 35, 75.
In conclusion, we have demonstrated that 1,3-cycload-
dition of relatively unstable nitrile oxides can be conve-
niently carried out in ionic liquids opening new
possibilities towards the synthesis of new potential con-
formationally constrained glutamic acid analogues or
arrays of other polyfunctionalized isoxazolines.

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D. Conti et al. / Tetrahedron Letters 44 (2003) 5327–5330
9. Characterization of selected products: 3: oil; Rf 0.38
15: oil; Rf 0.60 (n-hex/ethyl acetate: 4/1); the NMR data
for 15 were collected at 200 MHz in CDCl3 at 25°C. In
order to define the structure of 15, the following experi-
(n-hex/ethyl acetate: 4/1); 1H NMR (200 MHz, CDCl3,
25°C): l 5.14 (dd, J=9.6 and 8.1 Hz, 1H, H-5), 4.37–4.18
(m, 4H, 2×OCH2CH3), 3.46 (d J=8.1 Hz, 2H, H-4),
1.40–1.22 (m, 6H, 2×OCH2CH3); MS: C9H13NO5, 216
[M+1]+.
ments were performed: H, 13C, DEPT, COSY. H NMR
(200 MHz, CDCl3, 25°C): l 7 33 (s, 5H, Ph), 5.25–5.17
(m, 6H, CH2Ph, H-5), 4.32 (q, J=7.3 Hz, 2H,
OCH2CH3), 3.44–3.30 (four lines, A part of an ABX
system, 1H, CH2O) 3.04–2.94 (four lines, B part of an
ABX system, 1H, CH2O), 2.91–2.82 (four lines, A part of
an ABX system, 1H, H-3) 2.72–2.60 (four lines, B part of
an ABX system, 1H, H-3), 1.34 (t, J=7.3 Hz, 3H,
1
1
5: oil; Rf 0.33 (n-hex/ethyl acetate: 4/1); 1H NMR (200
MHz, CDCl3, 25°C): l 7.34 (s, 5H, Ph) 5.24–5.14 (m, 6H,
CH2Ph, H-5), 4.32 (q, J=7.2 Hz, 2H, OCH2CH3), 3.46
(d, J=8.7 Hz, 2H, H-4), 1.33 (t, J=7.2 Hz, 3H,
OCH2CH3); MS: C14H15NO5, 278 [M+1]+.
8: oil; Rf 0.46 (n-hex/ethyl acetate: 4/1); 1H NMR (200
MHz, CDCl3, 25°C): l 5.36 (dd, J=9.8 and 8.2 Hz, 1H,
H-5), 4.37 (q, J=7.2 Hz, 2H, OCH2CH3), 3.59 (d, J=8.2
Hz, 2H, H-4), 1.36 (t, J=7.2 Hz, 3H, OCH2CH3); 13C
NMR (200 MHz, CDCl3, 25°C): l 158.89 (COOEt),
151.10 (CꢀN), 68.00 (C-5), 62.86 (OCH2CH3), 39.94 (C-
4), 13.99 (OCH2CH3); MS: C7H8N2O3, 169 [M+1]+.
9: oil; Rf 0.17 (n-hex/ethyl acetate: 7/3); 1H NMR (200
MHz, CDCl3, 25°C): l 5.11–4.96 (m, 1H, H-5), 4.36 (q,
J=7.2 Hz, 2H, OCH2CH3), 3.52–3.37 (four lines, A part
of an ABX system, 1H, CH2CN) 3.17–3.05 (four lines, B
part of an ABX system, 1H, CH2CN), 2.74 (d, J=5.8 Hz,
2H, H-4), 1.35 (t, J=7.2 Hz, 3H, OCH2CH3); MS:
C8H10N2O3, 183 [M+1]+.
OCH2CH3); 13C NMR:
l 169.19 (COOBn), 160.33
(COOEt), 151.42 (CꢀN), 135.28 (ipso), 128.51, 128.31,
128.17 (Ph), 79.25 (C-5), 66.68 (CH2Ph), 61.97
(OCH2CH3), 39.37 (C-4), 38.65 (CH2COOBn), 13.96
(OCH2CH3); MS: C15H17NO5, 292 [M+1]+.
1
18: oil; Rf 0.17 (n-hex/ethyl acetate: 1/1); H NMR (200
MHz, CDCl3, 25°C): l 7.29 (s, 5H, Ph) 6.91 (bb, 1H,
NH), 6.58 (bb, 1H, NH), 5.08 (t, J=8.5 Hz, 1H, H-5),
4.49 (d, J=6.0 Hz, 2H, CH2CH(CH3)2), 3.58 (s, 2H,
CH2Ph), 3.20–3.02 (m, 2H, H-4), 1.83–1.69 (m, 1H,
CH2CH(CH3)2), 0.90 (s, 3H, CH2CH(CH3)2), 0.86 (s, 3H,
CH2CH(CH3)2); MS: C16H21N3O3, 304 [M+1]+.
10. In some cases the formation of furoxane 4 could not be
prevented, thus yields were lower. Nevertheless, as furox-
ane remained preferentially in the ionic liquid, the prod-
ucts could be isolated pure without chromatography.
11. The rate acceleration of the cycloaddition of imidates
derived from diethylmalonate and electron rich aromatic
aldehydes in ionic liquid has been reported: Dubreuil, J.
F.; Buzureau, J. P. Tetrahedron Lett. 2000, 41, 7351.
1
12: oil; Rf 0.40 (n-hex/ethyl acetate: 4/1); H NMR (200
MHz, CDCl3, 25°C): l 6.68 (d, J=7.3 Hz, 1H, H-5), 4.25
(q, J=7.0 Hz, 2H, OCH2CH3), 3.43–3.30 (four lines, A
part of an ABX system, 1H, H-4) 3.15–3.05 (four lines, B
part of an ABX system, 1H, H-4), 1.96 (s, 3H, OCH3),
1.26 (t, J=7.0 Hz, 3H, OCH2CH3); MS: C8H11NO5, 202
[M+1]+.