Regio- and stereospecific ring opening of 1,1-dialkyl-2-(aryloxymethyl) aziridinium salts by bromide

Article abstract of DOI:10.1039/b518298k

Enantiomerically pure 2-(aryloxymethyl)aziridines are efficiently transformed into chiral N-(2-bromo-3-aryloxypropyl)amines via a regio- and stereospecific ring opening of the intermediate aziridinium salts, and the experimental results are rationalized o

Full text of DOI:10.1039/b518298k

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Regio- and stereospecific ring opening of 1,1-dialkyl-2-
(aryloxymethyl)aziridinium salts by bromide{
Matthias D’hooghe,a Veronique Van Speybroeck,b Michel Waroquierb and Norbert De Kimpe*a
Received (in Cambridge, UK) 4th January 2006, Accepted 15th February 2006
First published as an Advance Article on the web 2nd March 2006
DOI: 10.1039/b518298k
the design of asymmetric syntheses towards chiral amines is
contemplated starting from chiral 2-substituted aziridines such as
1. Although the ring opening of aziridinium salts by halides has
been studied in the past,3 only very few reports dealing with the
stereochemistry of this type of reaction have been published,4 in
contrast with the study of the ring opening of activated
aziridines.1d Up to now, only 2-(alkoxycarbonyl), 2-phenyl and
2-methyl monosubstituted aziridinium salts (besides some di- and
trisubstituted aziridinium salts) have been studied in terms of
stereochemistry in ring opening reactions with fluoride, chloride or
iodide (but never bromide), affording the corresponding b-haloa-
mines as a result of a regioselective C–N cleavage at the more
hindered carbon atom or at the benzylic position. In this
communication, the ring opening of a novel type of substrate,
i.e. chiral 2-(aryloxymethyl)aziridinium salts, by bromide will be
studied for the first time in terms of regio- and stereoselectivity,
resulting in an efficient approach towards chiral N-(2-bromo-3-
aryloxypropyl)amines with diverse applications. The experimental
results are rationalized on the basis of some high level ab initio
calculations on the transition states and reactants of the various
routes as depicted in Scheme 1.
Enantiomerically pure 2-(aryloxymethyl)aziridines are effi-
ciently transformed into chiral N-(2-bromo-3-aryloxypropyl)
amines via a regio- and stereospecific ring opening of the
intermediate aziridinium salts, and the experimental results are
rationalized on the basis of some high level ab initio
calculations.
The aziridine moiety represents one of the most valuable three-
membered ring systems in organic chemistry due to its widely
recognized versatility as a building block towards a large variety of
ring opened or ring expanded amines.1 Moreover, regio- and
stereocontrolled ring opening reactions of chiral aziridines
constitute useful tools in asymmetric synthesis for the preparation
of chiral nitrogen-containing target compounds.2
Unactivated aziridines, i.e. aziridines without an electron-
withdrawing group at nitrogen, can easily be transformed into
aziridinium salts upon treatment with alkyl halides, which are
subsequently opened by a suitable nucleophile (usually the counter
ion). As depicted in Scheme 1, the reaction of a chiral aziridine 1
with an alkyl halide may lead to three different amines 4–6
depending on the reaction mechanism. In this way, the initial chiral
center at the substituted aziridine carbon atom can be retained
(pathway a, amine 4), inverted (pathway b, amine 5) or racemized
(pathway c, amine 6). Consequently, the elucidation of the
underlying reaction mechanism is of utmost importance when
Enantiomerically pure 2-(hydroxymethyl)aziridines 7 and 10
were easily tosylated using 1.05 equivalents of tosyl chloride in
CH2Cl2 in the presence of Et3N and a catalytic amount of DMAP,
affording the corresponding 2-(tosyloxymethyl)aziridines 8 and 11
in high yields after stirring for 4 hours at room temperature
(Scheme 2). The latter aziridines 8 and 11 were subsequently
transformed into 2-(aryloxymethyl)aziridines 9 and 12 upon
treatment with 2.2 equivalents of 3-chlorophenol or 4-methoxy-
phenol in DMF–acetone (1 : 1) in the presence of K2CO3 and
reflux for 20 hours (Scheme 2).5 In the latter reaction, the tosylate
is displaced by a phenolate ion via an SN2 process at the tosylated
carbon atom, without affecting the chirality of the aziridine carbon
atom, in analogy with the previously reported substitution by
methoxide.6 2-(Aryloxymethyl)aziridines 9 and 12 represent a
novel class of compounds and are valuable substrates for the
synthesis of a large variety of different aryloxypropylamines, the
latter being of significant interest due to their diverse biological
activities and their applicability in medicinal chemistry.7
Subsequently, aziridines 9 and 12 were exclusively converted
into b-bromoamines 14 and 16 upon treatment with an aryl
bromide in refluxing acetonitrile (Scheme 3) (see ESI{) as a useful
elaboration of a formerly reported ring opening reaction of
Scheme 1
aDepartment of Organic Chemistry, Faculty of Bioscience Engineering,
Ghent University, Belgium. E-mail: norbert.dekimpe@UGent.be;
Fax: (+32) 9 264 6243; Tel: (+32) 9 264 5951
2-(bromomethyl)aziridines
towards
N-(2,3-dibromopropyl)
bCentre for Molecular Modeling, Laboratory of Theoretical Physics,
Ghent University, Belgium. Fax: (+32) 9 264 6697; Tel: (+32) 9 264 6558
{ Electronic supplementary information (ESI) available: Spectral data of
compounds 9a, 12, 14a and 16. See DOI: 10.1039/b518298k
amines.8 Only one analogous substrate has been reported in a
ring opening reaction with iodide, although in this case the ring
opening of the chiral 2-(hydroxymethyl)aziridinium salt took place
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Scheme 2
Scheme 3
at the unsubstituted carbon instead of at the more hindered
position.9 The observed regiospecificity can be explained consider-
ing a nucleophilic attack of bromide at the more hindered carbon
atom of the aziridinium intermediates 13 and 15, giving rise to
2-bromopropylamines 14 and 16. As depicted in Scheme 1, the
formation of b-bromoamines 5 and 6 can be the result of an SN2
reaction (pathway b) or an SN1 process (pathway c), resulting in
inversion or racemization of the chiral center, respectively.
However, in all cases one single isomer was isolated, based on
NMR spectroscopy, pointing to the conclusion that this
transformation can only be described by an SN2 process
(Scheme 1, pathway b). If an initial ring opening of the
intermediate aziridinium salt had taken place (Scheme 1, pathway
c), neutralization by bromide of the planar carbocation thus
formed would result in the formation of the two diastereomers in
the same reaction mixture. Based on detailed spectroscopic
analysis, no traces of b-bromoamine 16 could be detected after
reaction of aziridine 9a with benzyl bromide, and vice versa.
Apparently, these reactions proceed through the formation of a
transition state TSb (Fig. 1), affording the corresponding
b-bromoamines 18 in a regio- and stereospecific way by attack
of bromide at the more hindered aziridine carbon atom C2 of
intermediate 17 via an SN2 pathway. This hypothesis was further
validated by performing ab initio calculations on the aziridinium
intermediate 13 and the transition states for the proposed reaction
routes in Scheme 1. The optimization was performed at the
MPW1B95/6-31 + g(d) level of theory, which is known to give
reliable estimates of the geometries.10 The reaction barriers were
furthermore obtained at the MPWB1K/6-31 + g(d) level which is
parametrized to give reliable reaction barriers.10 Moreover we have
tested a variety of other electronic levels and the selected methods
have been found most suitable. Also the effect of solvent is taken
into account, explicitly by surrounding the reactive center of the
complexes with two acetonitrile molecules and implicitly by
embedding all structures in a polarizable medium characterized
by a fixed dielectric constant which is typical for acetonitrile (i.e.
e 5 36.64). The calculations were performed in Gaussian 03.11
Approaching the aziridinium cation with the bromide ion leads to
a stable intermediate (17 in Fig. 1) on the potential energy surface.
The C–N bond lengths of the aziridinium cation are substantially
different, the one involving the substituted carbon atom being
longer (C2–N 5 1.50 s; C3–N 5 1.48 s, cf. Fig. 1). The weakening
of the C2–N bond upon substitution gives a preliminary indication
that nucleophilic attack could be favourable at the substituted
center. The aziridinium cation keeps almost exactly its isolated
geometry by approaching it with a bromide anion. Moreover, the
stabilization energy of the two approaching species is substantial
(405 kJ mol21, cf. SE in Fig. 2). Both arguments make any
suggestion of an SN1 substitution reaction very doubtful.
Furthermore, the coordination of the intermediate by solvent
molecules is highly exothermic as the coordination solvation
energy (CSE in Fig. 2) amounts to 93 kJ mol21 for two acetonitrile
Fig. 1
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relevant moiety in amines 14 and 16, their preparation might be of
importance as target compounds or as substrates for further
elaboration. The versatility of these compounds as substrates in
organic synthesis is currently under investigation, and will be
communicated in due course.
In conclusion, it has been demonstrated that 2-(aryloxymethyl)
aziridinium salts can be opened in a regio- and stereospecific way
by bromide to give N-(2-bromo-3-aryloxypropyl)amines, in
accordance with an SN2 type reaction mechanism. This methodo-
logy constitutes a novel protocol for the design of chiral syntheses
towards substituted aminopropane derivatives as biologically
relevant targets in medicinal chemistry.
Fig. 2 Energy profile for reaction route a and b with SE the stabilization
energy and CSE the coordination solvation energy as defined in the text.
The energies are relative to the isolated species.
Notes and references
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5 Spectral data of 9a and 12: see ESI{.
Fig. 3 Transition state for route b as depicted in Scheme 1.
molecules. More details about the effects of solvation can be found
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routes were calculated (pathway a and b in Scheme 1). Both
transition states are consistent with an SN2 mechanism
(C3–N 5 1.77 s and C3–Br 5 2.73 s for b; C2–N 5 1.70 s
and C2–Br 5 2.68 s for a). The reaction barriers for pathway a
and b amount to 76 and 70 kJ mol21, respectively (cf. Fig. 2). The
transition state for route b is shown in Fig. 3. Our theoretical
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properly embedded in a continuous dielectric medium was the
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be altered depending on the molecular environment used, which is
currently under investigation. A previous theoretical study on the
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N-(2-Halo-3-aryloxypropyl)amines have been reported to exhi-
bit a variety of biological activities, resulting in the application of
analogous compounds as e.g. antidepressants, antimicrobial and
antifungal agents.14 Due to the presence of such a biologically
1556 | Chem. Commun., 2006, 1554–1556
This journal is ß The Royal Society of Chemistry 2006