Opening of azetidinium ions with C-nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2007.10.105

The nucleophilic opening of functionalized azetidinium ions by C-nucleophiles was screened. Malonate and cyanide anions reacted in a highly regio- and chemoselective way leading to functionalized pure amines. The success of this reaction was found to be h

Full text of DOI:10.1016/j.tetlet.2007.10.105

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Tetrahedron Letters 48 (2007) 9180–9184
Opening of azetidinium ions with C-nucleophiles
Franc¸ois Couty,* Olivier David and Bruno Drouillat
Institut LAVOISIER, UMR CNRS 8180, Universite´ de Versailles, 45, Avenue des Etats-Unis, 78035 Versailles Ce´dex, France
Received 25 July 2007; revised 12 October 2007; accepted 19 October 2007
Available online 25 October 2007
Abstract—The nucleophilic opening of functionalized azetidinium ions by C-nucleophiles was screened. Malonate and cyanide
anions reacted in a highly regio- and chemoselective way leading to functionalized pure amines. The success of this reaction was
found to be highly dependent on the basicity of the involved nucleophiles and the competitive reactions induced by too basic
reagents were identified.
Ó 2007 Elsevier Ltd. All rights reserved.
The versatility of aziridines as significant building blocks
has been extensively demonstrated.1 Not only are these
strained nitrogen heterocycles able to react with a wide
range of heteronucleophiles but they can also be opened
by C-nucleophiles such as Grignard reagents,2 enolates,3
enamines4 and alkenes5 leading to the corresponding
opened product with concomitant C–C bond formation,
thus opening avenues for the synthesis of nitrogen-
containing compounds. In contrast, their higher homo-
logues, the azetidines, including an additional carbon
atom, have been much less studied as electrophilic syn-
thons. Two main reasons can explain this point: first,
due to the lower strain of the four-membered ring com-
pared to the three-membered ring, nucleophilic opening
requires strong activation of the intracyclic nitrogen
atom. Secondly, efficient synthetic access to these
heterocycles, particularly in enantiomerically pure form,
has not been developed to the same extent as for
aziridines.6
be reductively opened in a regio- and chemoselective
manner by different sources of hydride.8 In continua-
tion, considering that the formation of a C–C bond is
of utmost importance in organic synthesis, we decided
to explore the possibility of the nucleophilic opening
of such azetidinium ions by a nucleophilic carbon atom
(Scheme 1) since this reaction would give access to origi-
nal amino acids. Such nucleophilic openings have been
very scarcely reported, and the isolated examples in
the literature concern carbanions stabilized by adjacent
phosphorous moieties9 or butyllithium.10 In addition,
the question of regioselectivity or compatibility with
other functional groups present on the azetidinium ring
has never been addressed, to our knowledge.
The intrinsic problem associated with the above reaction
is the basicity of the carbon nucleophile, that can lead to
a competitive abstraction of the proton on the carbon of
the azetidinium bearing the functional group, thus
leading to a nitrogen ylide. Such ylides have been
recently studied by us.11 To address this problem, we
first selected azetidinium trifluoromethanesulfonate 2,11
bearing a nitrile moiety, and we reacted this compound
In our continuing interest in the chemistry of azetidines
and azetidinium ions, we have recently studied in detail
the regioselectivity of the nucleophilic opening of substi-
tuted azetidinium ions 1 bearing functional groups (FG:
CN, CO2Et) with various heteronucleophiles such as
amines, azide anions and acetate anions.7 In these
strained ammoniums, the activation of the nitrogen
atom is sufficient to allow smooth opening by an exter-
nal nucleophile in a regioselective manner. We also
demonstrated that these valuable building blocks could
FG
N
Regioselectivity ?
Compatibility with the presence
of functional groups such as CN or CO2Et ?
1
Nucleophilic
carbon
Keywords: Azetidines; Azetidinium ions; Strain.
*
Scheme 1. Can functionalized azetidinium ions be opened by
Corresponding author. Tel.: +33 139254455; fax: +33 139254452;
C-nucleophiles?
e-mail: couty@chimie.uvsq.fr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.105

F. Couty et al. / Tetrahedron Letters 48 (2007) 9180–9184
Table 1. Reaction of azetidinium ion 2 with C-nucleophiles
9181
Carbon nucleophile
CN
-
N
, TfO
Me Bn
2
Entry
1
Conditions
Product(s)
Yielda (%)
Bn
OLi
Ph
MeN
1.5 eq.
32
Ph
NC
Generated from LDA,
40 ˚C to rt, THF
3
O
OLi
Ph
1.5 eq.
2
3
b
b
44
Generated from LiHMDS,
40 ˚C 2 h, THF
OLi
CO Et
2
Me
, 1.5 eq.
3
4
—
—
Generated from LiHMDS
rt, 1 h, THF
ONa
CO Et
2
Me
, 1.5 eq.
Generated from NaH
DMF, 0 ˚C, 1 h
ONa
b
, 1.5 eq.
Generated from NaHMDS
20 ˚C to rt, 12 h, THF
Ot-Bu
5
6
—
31
Me
ONa
, 3 eq.
Ot-Bu
Generated from NaHMDS
20 ˚C to rt, 1 h, THF/DMF
N
Me
CN
4
CN
NMe
Bn
EtO C
2
O
ONa
CO Et
2
7
95c (ratio 5:6 = 75:25)
5
, 2 eq.
OEt
EtO
+
Generated from NaHMDS
rt, 15 h, THF
CN
CO Et
2
MeN
Bn
CO Et
2
6
CN
8
KCN, 3 equiv DMF, 1 h, rt
99
NC
NMe
Bn
7
a Yield of isolated product.
b A complex mixture was obtained.
c Combined yields.
ONa
OLi
CN
t
-BuO
Ph
CN
CN
+ PhCOMe
-
N
N
N
, TfO
Me
Me Bn
Me Bn
8
8
2
4
3
Scheme 2. Ketone and ester enolates deprotonate azetidinium ion 2.

9182
Table 2. Reaction of azetidinium trifluoromethanesulfonate salts with the enolate derived from diethyl malonatea and KCNb
Entry Substrate Product(s)
Yieldc (%)
Reactions with sodium diethylmalonate
F. Couty et al. / Tetrahedron Letters 48 (2007) 9180–9184
CO Et
Me
N
2
-
TfO
Bn Me
N
1
2
3
4
57
EtO C
Bn
2
10
9
Ph
EtO C
Ph
2
CO Et
CO Et
TfO
2
2
-
41
90
69
EtO C
2
N
12
Bn Me
N
Me
Bn
11
Ph
EtO C
Ph
2
CN
Bn
CN
TfO
EtO C
2
N
-
14
Me Bn
N
N
Me
13
CO Et
2
OBn
EtO C
OBn
Ph
2
N
-
TfO
Me
Me
15
Ph
16
Reactions with potassium cyanide
Ph
NC
CO2Et
Bn
17
N
Me
5
11
98 (ratio 17:18 = 43:57)
+
Me Ph
N
CO2Et
Bn
18
CN
Ph
NC
CN
Bn
6
7
13
88
19
Me
N
NC
CN
CN
-
TfO
N
66d
N
Me
Ph
Me
Me
20
Me
Ph
21
Ph
N
Me Ph
N
CN
91e
Me
CN
Me
NC
8
Me CN
23
Me Me
22
OBn
N
9
15
78
Me
Ph
24
Conditions:
a Sodium salt of diethyl malonate (generated from NaHMDS), 2 equiv, THF, rt, 15 h.
b KCN, 3 equiv, DMF, 0 °C, 1 h.
c Yield of isolated product.
d Contaminated by 12% of an inseparable regioisomer.
e Crude yield. This compound evolves to a zwitterion.

F. Couty et al. / Tetrahedron Letters 48 (2007) 9180–9184
9183
with a series of carbon nucleophiles. The results of these
experiments are collected in Table 1.
tonation. Another experiment demonstrates the crucial
importance of the pKa value of the involved C-nucleo-
phile: the treatment of azetidinium ion 15 with the
sodium enolate of t-butyl acetate gives enol ether 25 as
the major product. This azetidinium substrate, unable
to produce an ylide, undergoes a Hofmann elimination
with this basic nucleophile (Scheme 3).
This first set of experiments demonstrated that this
reaction is indeed possible but seems to be restricted to
a narrow range of C-nucleophiles. In fact, only the
sodium enolate derived from diethyl malonate and the
cyanide anion efficiently opened the azetidinium com-
pound (entries 7 and 8). In the first case, the reaction
smoothly occurred in THF at rt, with a fair regioselec-
tivity in favour of C-4 attack, while the opening with
cyanide anion was run in DMF and gave 7 with total
regioselectivity and almost quantitative yield. In
contrast, the sodium enolate derived from ethyl-
acetoacetate, tert-butyl acetate or acetophenone gave
complex mixtures (entries 1–6) from which epoxide 3
(entries 1 and 2) or azetidine 4 (entry 6) could be iso-
lated. The formation of these products unambiguously
proves that deprotonation of the azetidinium salt by
the reacting enolate occurs with these nucleophiles. As
a matter of fact, epoxide 3 results from a reaction
between azetidinium ylide 8 derived from 2 and aceto-
phenone, as previously described,12 and azetidine 4
results from a Sommelet–Hauser rearrangement of the
intermediate ylide 8,13 as depicted in Scheme 2.
Another parameter governing the efficiency of this reac-
tion is the degree of substitution of the azetidine ring.
This parameter can influence the regioselectivity of the
reaction (compare the exclusive C-4 attack by the
cyanide anion in substrates 2 and 13 and the slight drop
of regioselectivity with substrate 20), or even the reactiv-
ity (substrate 22 did not react with malonate anion, lead-
ing to decomposition products after protracted reaction
time). These hardly predictable results may reflect subtle
steric interactions generated during the SN2 process.
In conclusion, we have shown that azetidinium ions can
be opened in a highly regioselective way by malonate
and cyanide anions, and we have delineated the crucial
parameters for the success of this reaction. Synthetic
applications of this methodology are in progress in our
group.
Having established that sodium diethylmalonate and
potassium cyanide are suitable reagents to achieve our
goal, we next examined the scope of this reaction with
a range of different azetidinium ions. These results are
gathered in Table 2.
Acknowledgement
CNRS is acknowledged for generous support.
Except for azetidinium ion 11 reacting with cyanide
anion (entry 5), all the substrates studied here were
opened with a total to fair regioselectivity. This regiose-
lectivity is in accordance with our previous observations
involving heteronucleophiles,7 that is, regioselective
opening at C-4 with substrates free of substituent at this
position (entries 2–4, 6–7 and 9) and opening at C-2 with
substrate 22, bearing a methyl group at C-4 (entry 8).
The low regioselectivity observed with 11 reacting with
cyanide ion (entry 5) was previously observed with
acetate anion as nucleophile.7 This substrate reacted
however with sodiomalonate in a highly regioselective
Supplementary data
Supplementary data (experimental procedures and char-
acterization of compounds resulting from the nucleo-
philic opening of azetidinium ions by cyanide and
malonate anions) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.10.105.
References and notes
1
manner (entry 2), as proven by examination of the H
1. Hu, E. X. Tetrahedron 2004, 60, 2701.
2. Nenajdenko, V. G.; Karpov, A. S.; Balenkova, E. S.
Tetrahedron: Asymmetry 2001, 12, 2517.
3. Vicario, J. L.; Badia, D.; Carrillo, L. J. Org. Chem. 2001,
66, 5801.
4. Nishikawa, T.; Ishikawa, M.; Wade, K.; Isobe, M. Synlett
2001, 945.
5. Lapinsky, D. J.; Bergmeier, S. C. Tetrahedron 2002, 58,
7109.
NMR of the crude reaction mixture, thus highlighting
the crucial importance of the nucleophile involved in
the reaction. Importantly, in both experiments involving
cyanide or malonate anion, no epimerization at the
stereocentre of the azetidinium bearing the ester or the
cyano moiety could be observed. This demonstrates
that, under such conditions, these nucleophiles are either
unable to deprotonate the azetidinium salts or that the
rate of nucleophilic opening is much higher than depro-
6. For a review, see: Couty, F.; Evano, G.; Prim, D. Mini
Rev. Org. Chem. 2004, 1, 133.
7. Couty, F.; David, O.; Durrat, F.; Evano, G.; Lakhdar, S.;
Marrot, J.; Vargas-Sanchez, M. Eur. J. Org. Chem. 2006,
3479.
8. Couty, F.; David, O.; Durrat, F. Tetrahedron Lett. 2007,
48, 1027.
ONa
OBn
Ot-Bu
Me
Ph
OBn
N
N
-
TfO
Me
15
THF, rt
43%
´
´
9. (a) Helinski, J.; Skrzypczynski, Z.; Michalski, J. Tetra-
Ph
hedron Lett. 1995, 36, 9201; (b) Bakalarz-Jeziorna, A.;
25
´
Helinski, J.; Krawiecka, B. J. Chem. Soc., Perkin Trans. 1
Scheme 3. Hofmann elimination competes with nucleophilic opening.
2001, 1086.

9184
F. Couty et al. / Tetrahedron Letters 48 (2007) 9180–9184
10. Wills, M. T.; Wills, I. E.; Von Dollen, L.; Butler, B. L.;
Porter, J.; Anderson, A. G. J. Org. Chem. 1980, 45,
2489.
11. Couty, F.; David, O.; Larmanjat, B.; Marrot, J. J. Org.
Chem. 2007, 72, 1058.
12. Alex, A.; Larmanjat, B.; Marrot, J.; Couty, F.; David, O.
Chem. Commun. 2007, 24, 2500.
13. For an example of Sommelet–Hauser rearrangement
involving an azetidinium ion, see: Anderson, A. G.; Wills,
M. T. J. Org. Chem. 1968, 33, 3046.