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C. R. Chimie 19 (2016) 275e278Contents lists avaiComptes Rendus Chimie
www.sciencedirect.comFull paper/MemoireUnexpected synthesis of aziridines under Cu(I) catalyzed
Kinugasa conditions assisted by microwave irradiation
Heithem Abda a, Kaïss Aouadi a, *, Jihed Brahmi a, Moncef Msaddek a,
Sebastien Vidal b
a Universite de Monastir, Laboratoire de Synthese Heterocyclique, Produits Naturels et Reactivites, Faculte des Sciences de Monastir,
Avenue de l'Environnement, 5000 Monastir, Tunisia
b Universite de Lyon, Institut de Chimie et Biochimie Moleculaires et Supramoleculaires, UMR CNRS 5246, Laboratoire de Chimie
Organique 2-Glycochimie, Bâtiment Curien, 43 boulevard du 11 Novembre 1918, F-69622 Villeurbanne, Francea r t i c l e i n f o
Article history:
Received 21 June 2015
Accepted 17 September 2015
Available online 28 December 2015
Keywords:
Nitrone
Alkynes
1,3-Dipolar cycloaddition
Aziridines
Microwaves* Corresponding author.
E-mail address: kaiss_aouadi@hotmail.com (K. A
http://dx.doi.org/10.1016/j.crci.2015.09.009
1631-0748/© 2015 Academie des sciences. Publishea b s t r a c t
Cu(I)-catalyzed 1,3-dipolar cycloaddition between chiral nitrone and terminal alkynes
under microwave irradiation afforded a series of enantiopure aziridines with the creation
of two contiguous stereogenic centers.
© 2015 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.1. Introduction
1,3-Dipolar cycloaddition of nitrones is commonly used
in organic chemistry leading to valuable adducts containing
multifunctional nitrogen heterocyclic systems with various
properties. Cycloaddition with alkynes provides additional
access to heterocycles of potential biological interest [1e6].
The Kinugasa reaction [7] affords b-lactams from
substituted nitrones and copper(I) acetylides [8] and is
usually performed in organic solvents such as DMF, aceto-
nitrile, and sometimes in pure pyridine [7b]. Based on the
pioneering work of Kinugasa [7], we developed a Cu(I)-
catalyzed asymmetric synthesis of aziridines using termi-
nal acetylenes and a ()-menthone-based nitrone under
microwave irradiation. The expected outcome of this re-
action was the b-lactams issued from the known Kinugasa
reaction, but the intermediate isoxazoline was not stableouadi).
d by Elsevier Masson SAS. Aunder the conditions used and promptly rearranged into
the corresponding aziridines. Since the expected b-lactams
and aziridines displayed highly similar NMR data and
identical mass spectrometry analyses, the structures of the
obtained aziridines could be unambiguously identified
from X-ray crystallography data.
2. Results and discussion
The initial aim of this work was to prepare a series of b-
lactams based on the Kinugasa reaction [7]. Initially, the
Cu(I)-catalyzed cycloaddition of nitrone 1 with phenyl-
acetylene 2a (Scheme 1) in acetonitrile was performed at
room temperature (Table 1, entry 1). Unfortunately, the
reaction failed and each time the starting material
remained unchanged. Different conditions were applied
with additional microwave irradiation (Table 1, entries
2&6) using nitrone 1 and terminal alkynes 2a,d in DMF and
led mainly to aziridines 4a,d in relatively good yields. 1,3-
Dipolar cycloaddition of chiral nitrone 1 with phenyl-
acetylene 2a without copper and under microwavell rights reserved.
Scheme 1. Synthesis of aziridines 3 and 4.
Table 1
1,3-Dipolar cycloaddition of chiral nitrone 1 with terminal acetylenes 2aef under different conditions.
Entry Conditions Products (%)
1 2a CuI, CH3CN, NEt3, rt, 48 h NR*
2 2a CuI, DMF, mW, NEt3, 100 C, 2 h 4a (52%)
3 2a DMF, mW, NEt3, 100 C, 2 h 4a (63%)
4 2b CuI, DMF, mW, NEt3, 100 C, 2 h 3b (13%) 4b (53%)
5 2c CuI, DMF, mW, NEt3, 100 C, 2 h 3c (<21%a) 4c (52%)
6 2d CuI, DMF, mW, NEt3, 100 C, 2 h 4d (64%)
7 2e CuI, DMF, mW, NEt3, 100 C, 2 h 3e (12%) 4e (51%)
8 2f CuI, DMF, mW, NEt3, 100 C, 2 h NRb
a Compound 3c could not be isolated in a pure form, see the experimental section in the Supplementary Material.
b NR: No reaction was observed and starting materials were recovered.
H. Abda et al. / C. R. Chimie 19 (2016) 275e278276irradiation in DMF at 100 C provided mainly aziridine 4a
with a slightly higher yield (63%) than under Cu(I)-catalysis
(Table 1, entry 3). Unlike alkynes 2a,d, the reaction of chiral
nitrone 1 with terminal acetylenes 2bec,e under micro-
wave irradiation gave a readily separable epimeric mixture
of aziridines 3bec,e and 4bec,e (Table 1, entries 4,5, and 7).
Also, the reaction failed with propargyl acetate 2f (Table 1,
entry 8) probably due to the lower boiling point of thisFig. 1. Different paths to the aziridine or b-lactam residues dependinreagent and therefore poor availability in solution under
the conditions used.
As already described, formation of aziridines 3e4 could
be explained by the rearrangement of the 4-isoxazoline
intermediate A (Fig. 1), which was formed in situ and not
isolated, through a 1,4-migration thermal process [9]. The
low thermal stability of the NeO bond in the 4-isoxazoline
ring is most probably the reason for this rearrangementg on the initial regiochemistry of the 1,3-dipolar cycloaddition.
Fig. 2. ORTEP representation of the crystal structures of 3b [14] (left) and 4a
[15] (right).
Fig. 3. Partial 1H NMR spectra (400 MHz
H. Abda et al. / C. R. Chimie 19 (2016) 275e278 277under thermal activation [10]. Nevertheless, the ring-
opening rearrangement can also be triggered by Cu(I)-
species [11] or under radical conditions using Co2(CO)8
[12]. In the present case, the initial 4-isoxazoline interme-
diate A was therefore generated under thermal conditions
with a partial stereocontrol due to the hindered face of the
()-menthone-based nitrone 1 favoring the approach from
the opposite face to the isopropyl group. The presence of
CuI in the reaction mixture might have catalyzed the ring-
opening of the 4-isoxazoline A [11] but this process can also
occur spontaneously under heating being thermal [9] or
under microwave irradiation in the present case. Never-
theless, the thermal rearrangements occurred with total
selectivity towards the cis-isomers for the aziridine ring
system [9], while metal catalyzed aziridines were obtained
as diastereoisomeric mixtures with a major cis-isomer
[11,12]. These observations would therefore mean that the
CuI used in our reaction provided a mixture of di-
astereoisomers with the ratio observed in agreement with
these precedents.
The activation of the alkyne with copper was not
observed since this approach would have led to the oppo-
site regioisomer C, through the 6-membered ring metal-
locycle intermediate B [13]. This regioisomeric 4-
isoxazoline C would then evolve to the ketene intermedi-
ate D which would lead to the b-lactam E.
This difference in regioselectivity observed in the pres-
ence or not of Cu(I) species is probably the reason why the
expected Kinugasa-type b-lactams could not be observed.
The reaction proceeded as if the Cu(I)-acetylide
(ReC≡CeCu) could not be formed or was not reactive
enough with the ()-menthone-based nitrone 1, therefore
allowing the terminal alkyne to react with the nitrone.
The structures of diastereoisomers 3 and 4 have been
unambiguously established by X-ray diffraction analysis
and by NMR spectroscopy. The cis-configuration at the
aziridine ring was clearly identified in compound 3b
(Fig. 2). The diastereoisomers of the same alkyne (i.e. 3b/4b
or 3c/4c or 3e/4e) could not provide both crystals suitable
for X-ray diffraction and therefore the comparison of the
stereochemistry induced at the aziridine ring was possible
with the only two X-ray data collected for these com-
pounds 3b and 4a which crystallized and were of opposite
configuration at the aziridine ring., CDCl3) of compounds 3b and 4b.
H. Abda et al. / C. R. Chimie 19 (2016) 275e278278These X-ray crystallography results provided a basis for
the interpretation of NMR data. As exemplified for isomers
3b/4b (Fig. 3), the aromatic protons of the 4-methylphenyl
moieties resonating between 7.25 and 8.00 ppm provided
different signals. More importantly, signals resonating be-
tween 3.10 and 3.60 ppm can be considered as very
different from the trans-3b aziridine isomer to the cis-4b
isomer, both in terms of chemical shifts but also 3J coupling
constants. NMR data therefore clearly indicated the
different configurations observed by X-ray diffraction for
each diastereoisomer. This NMR pattern could be observed
for all other compounds in the series.
3. Conclusion
1,3-Dipolar cycloaddition of nitrones with alkynes pro-
vides access to either b-lactams under Cu(I)-catalysis or to
aziridines by simple heating. We have demonstrated here
that when a chiral nitrone is too hindered, the Cu(I)-
catalysis cannot act and therefore the thermal pathway
dominates the reaction and provides aziridines as diaste-
reoisomeric mixtures. The aziridines obtained could be
readily characterized by standard multi-dimensional NMR
spectroscopies and mass spectrometry. But the chirality
and structure of the aziridine backbone could be ascer-
tained by X-ray diffraction analysis of two diastereoisomers
of opposite configurations (cis and trans). The unmasking of
the menthone chiral auxiliary is now under investigation to
provide a novel entry towards chiral aziridine-based
amino-acids.
Appendix A. Supplementary data
Supplementary data related to this article can be found
at http://dx.doi.org/10.1016/j.crci.2015.09.009.
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contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.

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