COMMUNICATION
The preparation of stable aziridinium ions and their ring-openingsw
Yongeun Kim,a Hyun-Joon Ha,*a Sae Young Yunb and Won Koo Lee*b
Received (in Cambridge, UK) 29th May 2008, Accepted 26th June 2008
First published as an Advance Article on the web 24th July 2008
DOI: 10.1039/b809124b
The reaction of enantiomerically pure 2-substituted 1-phenyl-
ethyl-aziridine with methyl trifluoromethanesulfonate generated
a stable methylaziridinium ion, which was reacted with various
external nucleophiles, including nitrile, to yield synthetically
valuable and optically pure acyclic amine derivatives in a
completely regio- and stereoselective manner.
Small-ring compounds, including cyclopropane, oxirane and
aziridine, are valuable, not only because they are the constituents
of a number of important molecules, but because they are good
synthetic intermediates in the synthesis of acyclic molecules via
ring-opening reactions. Compared with cyclopropane and oxi-
rane, the chemistry of aziridine depends on the characteristics of
the substituent on the ring nitrogen, as well as the ring carbon.1
When the aziridine ring nitrogen has an electron withdrawing
substituent (EWG), such as a carbonyl or sulfonyl group, the
ring becomes less stable and more reactive towards nucleophiles
with respect to ring-opening.2 However, when the ring nitrogen
has an electron donating substituent (EDG), such as phenyl-
ethyl, the aziridine becomes more stable and less reactive than
that bearing a hydrogen or an electron withdrawing substituent.
Therefore, an aziridinium intermediate is always involved prior
to nucleophilic ring-opening reactions (Scheme 1).
Scheme 1 ring-opening reactions of aziridines.
of the limited range of applicable nucleophiles, we needed a
reliable method to generate an aziridinium ion that was stable
enough to survive in the presence of a counter-anion until the
addition of external nucleophiles for ring-opening.
One of the best counter-anions, with poor nucleophilicity
after the generation of an electrophilic aziridinium ion, is the
sulfonate anion, which is not reactive enough to break down
the aziridinium ions. This was tested by reacting methyl
trifluoromethanesulfonate with the substrate, 2R-[(1R)-phenyl-
ethyl]methoxymethylaziridine in CH3CN, leading to the
methylation of the aziridine ring nitrogen to provide the
corresponding aziridinium ion. We observed that all of the
1
peaks of the starting aziridine in the H NMR spectrum had
Since we successfully prepared both (2R)- and (2S)-N-a-
shifted downfield 10 min after adding methyl trifluoromethane-
sulfonate, from d 2.51, 1.66, 1.62 and 1.45 to d 4.02, 3.56, 3.47
and 2.94, with coupling constants originating from the unique
aziridine ring conformer. Generation of the aziridinium ion by
methylation was also possible with 2R-[(1R)-phenylethyl]aziri-
dine-2-carboxylate, with 1H NMR peaks shifted downfield
from 2.61, 2.26, 1.92 and 1.61 to 4.28, 3.51, 3.41 and 2.97,
with a slight change in the coupling constants. The peak
positions in the 1H NMR spectrum arising due to the
aziridinium ions were unchanged after up to 10 h at room
temperature under nitrogen. The configuration of the N-methy-
laziridinium ions is speculated to be that of 2, on the basis of
the crystalline structure of dicyano{[(1S)-(1-phenylethyl)aziri-
din-2-yl]methanolato-k2N,O}boron, showing that the ring ni-
trogen has a tetrahedral geometry, without much torsional
change to the aziridine ring (Scheme 2).7
methylbenzylaziridine-2-carboxylates on
a
multi-kilogram
scale, and in optically pure forms, we have been able to
synthesize various cyclic and acyclic nitrogen-containing mole-
cules with ring-opening or ring-expansion as a key step.3
However, there is always the drawback that the ring nitrogen
needs to be activated by a suitable electrophile to generate an
aziridinium ion prior to the nucleophilic ring-opening reactions.
Therefore, the source of applicable nucleophiles is limited to
reagents that can provide the necessary electrophiles, such as
carboxylic acids,4 acid chlorides5 and trimethylsilyl azide.6
These reagents provide proton, acyl and trimethylsilyl electro-
philes, respectively, to yield the corresponding aziridinium ions
prior to ring-opening by the anionic counter-nucleophiles,
carboxylate, chloride and azide. To overcome the drawback
a Department of Chemistry and Protein Centre for Bio-Industry,
Hankuk University of Foreign Studies, Yongin 449-791, Korea.
E-mail: hjha@hufs.ac.kr; Fax: +82 31-3304566;
2R-[(1R)-Phenylethyl]methoxymethylaziridine (1A) was
treated with methyl trifluoromethanesulfonate, followed by
reaction with NaN3, to yield a single regioisomer of ring-
opening product 3Aa in 89% yield (entry 1, Table 1). This led
us towards further development with other external nucleo-
philes, including acetate, morpholine and benzylamine, to give
the corresponding 3-acetyloxymethyl- (3Ab), morpholin-4-yl-
methyl- (3Ac) and 3-benzylaminomethyl- (3Ad) 2-amino-
propanes, respectively (entries 2–4, Table 1).
Tel: +82 31-3304369
b Department of Chemistry and Interdisciplinary Program of
Integrated Biotechnology, Sogang University, Seoul 121-742, Korea.
E-mail: wonkoo@sogang.ac.kr; Fax: +82 2-7010967;
Tel: +82 2-7058449
w Electronic supplementary information (ESI) available: 1H NMR
spectra of aziridinium salts (2) from the reaction of 1A and 1C with
methyl trifluoromethanesulfonate, synthetic procedure and character-
isation of all new compounds. See DOI: 10.1039/b809124b
ꢀc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 4363–4365 | 4363
Kim, Yongeun
