Tactics for the asymmetric preparation of 2-azabicyclo[3.1.0]hexane and 2-azabicyclo[4.1.0]heptane scaffolds

Article abstract of DOI:10.1016/j.tetlet.2011.03.026

In this contribution, two methods are presented for the removal of benzyl-type protecting groups attached to the nitrogen atom of 2-azabicyclo[3.1.0]hexane and 2-azabicyclo[4.1.0]heptane systems. The first, based on the Polonovski reaction, is suitable for [3.1.0] systems. The second relies on an elimination process, starting from derivatives of O-methyl phenylglycinol, and is more general in terms of the substrates tolerated. Secondary bicyclic cyclopropylamines, including enantiomerically pure molecules, can thus be accessed. These compounds are then ready for further functionalisation.

Full text of DOI:10.1016/j.tetlet.2011.03.026

Tetrahedron Letters 52 (2011) 2501–2504
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Tactics for the asymmetric preparation of 2-azabicyclo[3.1.0]hexane
and 2-azabicyclo[4.1.0]heptane scaffolds
Andrzej Wolan a, , Mohamad Soueidan a, Angèle Chiaroni a, Pascal Retailleau a, Sandrine Py b, Yvan Six a,
⇑
a Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
b Département de Chimie Moléculaire (SERCO) UMR-5250, ICMG FR-2607, CNRS Université Joseph Fourier, BP 53, 38041 Grenoble Cedex 09, France
a r t i c l e i n f o
a b s t r a c t
Article history:
In this contribution, two methods are presented for the removal of benzyl-type protecting groups
attached to the nitrogen atom of 2-azabicyclo[3.1.0]hexane and 2-azabicyclo[4.1.0]heptane systems.
The first, based on the Polonovski reaction, is suitable for [3.1.0] systems. The second relies on an elim-
ination process, starting from derivatives of O-methyl phenylglycinol, and is more general in terms of the
substrates tolerated. Secondary bicyclic cyclopropylamines, including enantiomerically pure molecules,
can thus be accessed. These compounds are then ready for further functionalisation.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 9 December 2010
Revised 21 February 2011
Accepted 4 March 2011
Available online 12 March 2011
Keywords:
Aminocyclopropanes
Chiral auxiliaries
Kulinkovich–de Meijere reaction
Organotitanium chemistry
Polonovski reaction
Bicyclic aminocyclopropanes are interesting molecules. Those
possessing a carboxylic acid function are constrained amino acids
that have found applications as organocatalysts or in the synthesis
of peptidomimetics.1 More generally, bicyclic aminocyclopropanes
may undergo various ring-opening transformations and are valu-
able precursors of more elaborate nitrogen-containing systems of
interest.2,3 In this context, a method for the synthesis of bicyclic
secondary cyclopropylamines 1 would be advantageous: function-
alisation of such scaffolds at the nitrogen atom is expected to be
straightforward. The preparation of various derivatives could thus
the possibility, in principle, to use the functional group G as a chiral
auxiliary to prepare enantiomerically pure aminocyclopropanes 1.
A seemingly straightforward approach would be the introduc-
tion of a benzyl-type protecting group and its later removal by a
metal-catalysed hydrogenation reaction. Indeed, such selective
R
G
O
N
( )n
R'
be achieved quickly, without having to repeat
a multi-step
R'
3
R
Kulinkovich-de Meijere reaction
sequence for each target molecule (Scheme 1). Moreover, chemical
functions that are not compatible with the cyclopropanation step,
usually performed using an organometallic reaction, could then be
introduced. The synthesis of complex aminocyclopropanes would
also be more convergent.
Our strategy consisted in using bicyclic tertiary aminocyclopro-
pylamines 2, with a selectively removable group, G at the nitrogen
atom, as precursors of 1. In turn, compounds 2 can be synthesised
from suitable N-alkenyl amide substrates 3 via the intramolecular
Kulinkovich–de Meijere reaction, a particularly expedient and gen-
eral titanium-mediated process.4,5 An advantage of this strategy is
R1
N
( )n
R'
R'
R'
R
R
N
R
R2
N
G
HN
( )n
( )n
( )n
2
1
etc.
Scheme 1. Synthesis of various 2-azabicyclo[3.1.0]hexanes and 2-azabicy-
clo[4.1.0]heptanes from common precursor 1.
⇑
Corresponding author at present address: Département de Chimie, UMR 7652,
CNRS/Ecole Polytechnique, 91128 Palaiseau, France. Tel.: +33 (0)1 6933 5979; fax:
+33 (0)1 6933 5972.
E-mail address: six@dcso.polytechnique.fr (Y. Six).
Present address: Department of Chemistry, Nicolaus Copernicus University,
Gagarina 7, 87-100 Torun´ , Poland.
Scheme 2. Attempted selective cleavage of the Bn group of 2a.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.026

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A. Wolan et al. / Tetrahedron Letters 52 (2011) 2501–2504
cleavage steps have been reported in the literature starting from
bicyclic N-benzyl aminocyclopropanes.6 However, when the bicy-
clic substrate 2a was submitted to these types of conditions,
opening of the cyclopropane ring was observed (Scheme 2). Similar
results have been described with analogous 2-azabicy-
clo[3.1.0]hexanes.7 An alternative method was thus needed.
Chemla and co-workers recently published a solution to the
same problem, using the reagent 1-chloroethyl chloroformate,
with low to moderate yields.7–9 This prompts us to report our
own preliminary findings. We have implemented two tactics, the
first based on the Polonovski reaction, and the second on an
elimination process.
The Polonovski reaction is a general transformation that can
convert tertiary N-oxides into N,N-disubstituted amides.10 In order
to ascertain whether this reaction could be applied to the cleavage
of a benzyl-type group as borne by our bicyclic aminocyclopro-
panes, we synthesised the N-oxides 4a and 4b from the corre-
sponding tertiary amines 2a and 2b, readily obtained in good
yields from the amides 3a and 3b (Scheme 3). Surprisingly and
very interestingly, the oxidation process occurred with complete
diastereoselectivity in both cases. The oxygen atom and the methyl
group are cis to each other in 4a as demonstrated unambiguously
Treatment of 4a with several acylating agents proved success-
ful, and the amides 5, 6 and 7 were isolated in moderate to good
yields. Most interestingly, using di-tert-butyl dicarbonate, the
Boc-protected amine 8 was obtained in excellent yield. Its conver-
sion into the HCl or TFA salts of the secondary amine 1a then
proceeded smoothly (Scheme 4).
However, this method was not successful when applied to the
homologous [4.1.0] bicyclic system 4b: treatment of this com-
pound with di-tert-butyl dicarbonate in CH2Cl2 at 20 °C delivered
a mixture of unidentified products.12
With a view to prepare enantiomerically pure 1a, and also to
circumvent the obstacle we had met with the homologous bicyclic
[4.1.0] system, we investigated another tactic relying on an elimi-
nation reaction of tertiary amines with a 2-methoxy-1-phenylethyl
substituent. This idea, which is reminiscent of multi-step methods
developed by several groups over the past 20 years,13–17 was first
tested on the simple substrate 9. Various reagents were scrutin-
ised, and tBuOK in DMSO gave the best results (Scheme 5).18,19
The Kulinkovich–de Meijere intramolecular reactions of the
amides 3c and 3d proceeded in 77% and 65% yields, respectively,
with virtually no control of the relative configurations by the chiral
(R)-2-methoxy-1-phenylethyl group (Scheme 6). The two diastere-
oisomers of the 2-azabicyclo[4.1.0]heptane 2d were readily sepa-
rated by silica gel flash column chromatography, and removal of
the chiral auxiliary upon treatment with tBuOK in DMSO afforded
the desired secondary amine enantiomers (S)- and (R)-1d in
moderate yields (Scheme 7). Their absolute configurations were
determined by single-crystal X-ray diffraction of (S)-1d,11 and their
by X-ray diffraction performed on
a single crystal of this
compound.11 It is assumed that the relative configuration of 4b is
the same as that of 4a.12
opposite [
a
]
values [À38.3 and +37.5 for the (S) and (R) com-
D
pounds respectively; c = 0.1, CHCl3] confirmed their enantiomeric
relationship.
Hence, the problem of the preparation of the secondary amines,
as well as the acquisition of both enantiomers, was solved in the
Scheme 3. Synthesis of the N-oxides 4a and 4b.
Scheme 5. Cleavage of the 2-methoxy-1-phenylethyl group by an elimination
pathway.
Scheme 6. Synthesis of the aminocyclopropanes 2c and 2d.
Scheme 4. Conversion of the N-oxide 4a into 1a and other secondary amine
derivatives.
Scheme 7. Synthesis of both enantiomers of the secondary amine 1d.

A. Wolan et al. / Tetrahedron Letters 52 (2011) 2501–2504
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case of the 2-azabicyclo[4.1.0]heptane system. In contrast, we
were not able to separate efficiently the two diastereoisomers of
the 2-azabicyclo[3.1.0]hexanes 2c, and, therefore, the elimination
tactic was of no advantage in this particular case. Consequently,
we investigated the use of a phenethyl chiral auxiliary that could
be removed using the Polonovski reaction. The alkenyl amide 3e
was converted, with poor diastereoselectivity, into the correspond-
ing aminocyclopropane 2e (Scheme 8). Again, the two diastereoiso-
mers of this compound proved extremely difficult to separate by
flash column chromatography, and work is currently under pro-
gress in our laboratory to identify a more suitable chiral auxiliary.
In spite of the disappointing results obtained in the simple
2-azabicyclo[3.1.0]hexane series, the example displayed in
Scheme 9 shows that the elimination method may nevertheless
be useful in the case of more substituted substrates. Indium-
mediated allylation of the imine,20 prepared from benzaldehyde
and (R)-2-methoxy-1-phenylethanamine, delivered the corre-
sponding secondary homoallylamines with moderate diastereose-
lectivity. Unfortunately, we were not able to separate them, and
the next step, an acylation reaction, raised difficulties, presumably
because of the high steric hindrance of the amine group.21 None-
theless, good conversion was achieved with AcCl/Et3N with
0.1 equiv of DMAP in CH2Cl2 at 20 °C. However, we were not able
to separate the two expected diastereoisomers 3f by flash column
chromatography, and the 1H and 13C NMR spectra proved extre-
mely difficult to analyse because of the presence of amide rotamers
and the likely restricted rotation of several bonds. We were not
sure whether they were contaminated with side-products, or not.
This, combined with the high steric hindrance of 3f, accounts for
Scheme 10. Applications of the aminocyclopropane scaffolds.
the low yield obtained in the next step, giving the mixture of
aminocyclopropane diastereoisomers 2f. The major diastereoiso-
mer, with the shown (R,R,S) absolute configuration deduced from
the (R,R) absolute configuration of the major diastereoisomer of
the secondary amine precursor, and of previous results obtained
in our laboratory,22 could be separated and submitted to the
tBuOK-mediated elimination reaction, delivering the expected
secondary amine (R,S)–1f ([a] + 33.5; c = 0.07, CHCl3). It is worth
noting that not only was the cyclopropane ring preserved, but also
the bond between the nitrogen atom and the intracyclic benzylic
carbon atom. Equally importantly, only one diastereoisomer of
the product was observed. Since epimerisation at the cyclopropane
chiral centres is very unlikely, this indicates that no epimerisation
occurred at the benzylic position either, and as a result (R,S)–1f
was enantiomerically pure.
Finally, the utility of our method is illustrated by the three
examples displayed in Scheme 10. The first one shows that the
amide 7 can be easily converted into the acyl iminium compound
10 by protonation with triflic acid. The other two examples, an SN2
reaction and a Michael-type reaction, are especially interesting
because the aminocyclopropane products 2g and 2h could not
have been synthesised using the Kulinkovich–de Meijere reaction
from the corresponding alkenyl amides. Indeed, it is well estab-
lished that ester and nitrile groups are more reactive than amides
towards the titanium complexes involved in this transformation.23
In conclusion, we have implemented two tactics for the prepa-
ration of enantiomerically pure 2-azabicyclo[3.1.0]hexane and
2-azabicyclo[4.1.0]heptane scaffolds. These scaffolds contain a
secondary amine moiety that can be functionalised to access di-
versely substituted bicyclic cyclopropylamines, including com-
pounds bearing sensitive functions that could not be obtained
directly via standard cyclopropanation methods. Our first tactic
consists in preparing bicyclic aminocyclopropanes with a benzyl-
type protecting group that is then removed by performing a Polo-
novski reaction from the corresponding N-oxide. This method is
poorly applicable to the 2-azabicyclo[4.1.0]heptane systems, but
gives excellent results with smaller 2-azabicyclo[3.1.0]hexane
bicycles. The second tactic, being more general, relies on the selec-
tive cleavage of a chiral 2-methoxy-1-phenylethyl group using
tBuOK in DMSO. This method does not affect other types of benzyl
groups and, as such, might find applications in a wider context.
Scheme 8. Intramolecular Kulinkovich–de Meijere reaction of 3e.
Acknowledgements
The authors thank Claire Madelaine and Justyna Kowalska-Six
for some early experiments. We are grateful to the Centre National
de la Recherche Scientifique and to the Institut de Chimie des
Substances Naturelles for financial support. We also wish to thank
the staff of the mass spectrometry and elemental analysis services
Scheme 9. Synthesis of enantiomerically pure cyclopropylamine (R,S)–1f.

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A. Wolan et al. / Tetrahedron Letters 52 (2011) 2501–2504
9. See also: Simpkins, L. M.; Bolton, S.; Pi, Z.; Sutton, J. C.; Kwon, C.; Zhao, G.;
Magnin, D. R.; Augeri, D. J.; Gungor, T.; Rotella, D. P.; Sun, Z.; Liu, Y.; Slusarchyk,
W. S.; Marcinkeviciene, J.; Robertson, J. G.; Wang, A.; Robl, J. A.; Atwal, K. S.;
Zahler, R. L.; Parker, R. A.; Kirby, M. S.; Hamann, L. G. Bioorg. Med. Chem. Lett.
2007, 17, 6476–6480.
of the Institut de Chimie des Substances Naturelles for their contribu-
tion to this work.
Supplementary data
10. Li, J. J. Name reactions, a collection of detailed reaction mechanisms, third ed.;
Springer: Heidelberg, 2006.
Supplementary data (typical experimental procedures; X-ray
crystal structures of 4a and (S)-1d.HCl; discussion with respect to
the exclusive formation of one diastereoisomer of the N-oxides
4a and 4b; proposed explanation for the differences of behaviour
observed in the subsequent Polonovski reactions; NMR spectra of
all compounds) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2011.03.026.
11. Crystallographic data (excluding structure factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 802584 and 802585. Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: +44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.Uk).
12. See the Supplementary data for a discussion and further details.
13. Multi-step conversion of a phenylglycinol moiety into an
a-aminohydrazone,
which then undergoes fragmentation: Mehmandoust, M.; Marazano, C.; Das, B.
C. J. Chem. Soc., Chem. Commun. 1989, 1185–1187.
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Tetrahedron: Asymmetry 1992, 3, 511–514; (b) Nyzam, V.; Belaud, C.;
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products, or of the corresponding acetamides 3f. This would have enabled us to
synthesise both enantiomers of the secondary cyclopropylamine 1f.
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