Insight into the regioselectivity of nucleophilic ring-opening of azetidinium ions containing quaternary carbon atoms

Article abstract of DOI:10.1002/ejoc.201200890

A set of azetidinium ions each bearing a quaternary carbon atom α to the nitrogen atom were synthesized. These compounds were treated with three different nuclophiles: azide, cyanide and acetate anions. Examination of the regioselectivity in the ring-opening reactions demonstrated that attack at the quaternary position is intrinsically favored over that at the secondary position. However, these S_N2 reactions are highly sensitive to steric crowding, which can counterbalance the natural trend to react at the quaternary carbon. Dissymmetric azetidinium ions with secondary and quaternary carbon atoms α to the nitrogen atoms were treated with cyanide, azide and acetate anions. The regioselectivity of the ring opening tends to favour opening at the quaternary carbon, but these reactions are highly sensitive to steric hindrance. Complete inversion at the quaternary centres demonstrates that clean S_N2 reactions operate.

Full text of DOI:10.1002/ejoc.201200890

Job/Unit: O20890
/KAP1
Date: 05-09-12 18:42:02
Pages: 9
FULL PAPER
DOI: 10.1002/ejoc.201200890
Insight into the Regioselectivity of Nucleophilic Ring-Opening of Azetidinium
Ions Containing Quaternary Carbon Atoms
Bruno Drouillat,[a] Karen Wright,[a] Olivier David,[a] and François Couty*[a]
Keywords: Nitrogen heterocycles / Small ring systems / Nucleophilic substitution / Regioselectivity / Reaction mechanisms
A set of azetidinium ions each bearing a quaternary carbon
atom α to the nitrogen atom were synthesized. These com-
pounds were treated with three different nuclophiles: azide,
cyanide and acetate anions. Examination of the regioselec-
tivity in the ring-opening reactions demonstrated that attack
at the quaternary position is intrinsically favored over that
at the secondary position. However, these SN2 reactions are
highly sensitive to steric crowding, which can counterbal-
ance the natural trend to react at the quaternary carbon.
cult, but our attention was attracted by two recent literature
reports describing ring opening of azetidinium ions at qua-
ternary centres. The first was from our group and involves
the regioselective ring opening of bicyclic azetidinium ion 2
(Scheme 1) at the quaternary position, in competition with
a tertiary process, to lead to an azepane.[12] The second was
recently described by Wang et al.[13] and involves the ring
opening of monocyclic azetidinium ion 4 (Scheme 1), lead-
ing to α-quaternary carboxamide 5 with clean inversion of
configuration. This last result particularly attracted our at-
tention, because here the quaternary position competes ef-
ficiently with the secondary position in the azetidinium ion,
which seems quite unexpected at first glance without the
intervention of a SN1 mechanism. Furthermore, our own
experience in the chemistry of azetidinium ions shows that
nucleophilic attack at a methylene position is usually fav-
oured over that at a monosubstituted position, which can
be expected as the normal rule for SN2 reactions.
Introduction
Azetidinium ions 1 (Figure 1) are emerging as useful
electrophilic building blocks for the synthesis of nitrogen-
containing molecules. Unlike their three-membered lower
homologues the aziridinium ions, which because of their
highly reactive natures are most commonly generated in
situ,[1] these ammonium salts can be conveniently prepared
and isolated as stable trifluoromethanesulfonate salts. These
strained ammonium ions react smoothly with a wide range
of heteronucleophiles (amines,[2] alkoxides or alcohols,[3]
phenols,[4] carboxylates,[5] sulfur nucleophiles,[6] phosphorus
nucleophiles[7] and halides[8]), with hydride anions[9] and
with carbon nucleophiles such as cyanide ions or sodium
malonate.[10] Regioselectivity in these ring-opening reac-
tions is usually very high and is basically governed by steric
control, as in SN2 reactions. Moreover, clean Walden inver-
sion at substituted positions, coupled with easy access to
enantiomerically pure azetidines[11] incorporating diverse
functional groups, makes these electrophilic building blocks
particularly attractive.
Figure 1. Nucleophilic opening of an azetidinium ion.
Stereoselective formation of C-quaternary centres is one
of the major goals in organic synthesis. SN2 reactions at
quaternary carbon atoms are known to be extremely diffi-
[a] Institut Lavoisier de Versailles, UMR 8180, Université de
Versailles St-Quentin en Yvelines,
45, av. des Etats-Unis, 78035 Versailles Cedex, France
Fax: +33-1-39254452
E-mail: couty@chimie.uvsq.fr
Homepage: http://www.ilv.uvsq.fr/research/Syre/syre.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200890.
Scheme 1. Isolated examples of regioselective nucleophilic opening
of azetidinium ions at quaternary positions.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O20890
/KAP1
Date: 05-09-12 18:42:02
Pages: 9
B. Drouillat, K. Wright, O. David, F. Couty
FULL PAPER
These isolated examples, together with the ease of prepa-
ration of azetidinium ions from azetidines and the emerging
synthetic routes to enantiomerically pure azetidines bearing
quaternary centres α to their nitrogen atoms,[14] suggest that
generalization of such ring-opening reactions would repre-
sent a unique tool for the construction of quaternary
centres with predictable stereochemistry. We therefore de-
cided to study the scope of these reactions in more detail,
by varying the natures both of the substituents on the azet-
idine ring and of the reacting nucleophiles.
Results and Discussion
Some representative azetidines 6–11 (Figure 2), each con-
taining a quaternary centre, were first selected as substrates.
New spiroazetidines 6 and ester 7 were prepared by the
route shown in Scheme 2. Esters 7 and 8,[15] bearing a
phenyl or a methyl group, respectively, at their quaternary
positions, were selected in order to study the influences of
these substituents on the regioselectivity of the ring open-
ing. Alcohol 9, obtained by reduction of 8,[15] was included
in order to allow study of the influence of a non-EWG
group. Finally, the enantiomerically pure nitrile 10[14c] and
ester 11[14c] were selected in order to permit examination of
the stereospecificity of the ring opening.
Scheme 2. Syntheses of azetidines 6 and 7.
the product of a highly diastereoselective elimination of an
allylic proton (this compound was obtained as a single iso-
mer of undetermined geometry for the trisubstituted alk-
ene).
Figure 2. Structures of the α-quaternary azetidines selected for this
study.
All of these substrates were next alkylated with methyl
trifluoromethanesulfonate (MeOTf) in dichloromethane at
room temp. to afford the corresponding quaternary azetid-
inium salts 18–23 (Figure 3) in good yields and with low to
average diastereoselectivities. These ammonium salts proved
to be stable and could be conveniently isolated and stored
without noticeable decomposition. These compounds were
each next treated under standardized conditions (r.t.,
DMF) with three different nucleophiles: caesium (or so-
dium) acetate, potassium cyanide and sodium azide. The
structures of the obtained products are shown in Table 1.
Figure 3. Structures of the α-quaternary azetidinium salts selected
for this study.
In terms of regioselectivity, exclusive attack at the quater-
These results show that the regioselectivity of the ring open- nary position was observed in the cases of positions bearing
ing depends both on the nature of the azetidinium substrate both an ester and a methyl, phenyl or allyl group (Entries 4,
and, less expectedly, on the nature of the incoming nucleo- 7 and 14, respectively). In the last case a single diastereoiso-
phile. The following observations can be highlighted: with mer was obtained, which demonstrates the occurrence of a
the highly nucleophilic azide anion, reactions were fast and clean SN2 reaction. In the case of spiroazetidinium 18, how-
gave fair to excellent yields of ring-opened products in all ever, the regioselectivity was completely reversed (Entry 1),
cases except for that of the highly encumbered azetidinium whereas in that of dialkyl-substituted azetidinium 21 both
ion 22 (Entry 13), for which only diene 39 was produced as regioisomers were obtained (Entry 10).
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20890
/KAP1
Date: 05-09-12 18:42:02
Pages: 9
Regioselective Ring-Opening of Azetidinium Ions
Table 1. Results of ring opening of azetidinium ions 19–23 with
azide, cyanide and acetate anions.
Table 1. (Continued).
nary position was strongly diminished. By comparing En-
tries 4/5, 7/8 and 10/11 we can see that opening at the qua-
ternary position was never exclusive as it had been with the
azide anion, and was only favoured in the case of azetidin-
ium salt 19 (Entry 5).
Finally, when a poor nucleophile such as an acetate
anion was used, yields were much lower and elimination
could be observed as a side reaction (Entry 3). Nucleophilic
opening at the less hindered position (Entries 6, 9) was fav-
oured, except in the case of azetidinium salt 21 (Entry 12),
for which only ring-opening at the quaternary position
could be detected in the crude reaction mixture.
From a practical viewpoint, assignment of the natures of
When the less nucleophilic cyanide anion was involved, the regioisomers in the case of nucleophilic opening by an
the tendency to favour nucleophilic opening at the quater- azide anion is not a trivial task. Here, HMBC experiments
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O20890
/KAP1
Date: 05-09-12 18:42:02
Pages: 9
B. Drouillat, K. Wright, O. David, F. Couty
FULL PAPER
allowed us to determine the natures of the regioisomers. nucleophile, then the other regioisomer can be produced,
Additionally, tertiary azide 31 was converted into the acet- together with undesired products resulting from side reac-
amide 41 (Scheme 3), in which no significant shift of the tions such as elimination (Entries 3, 13). Only one entry in
methylenic protons was observed, thus confirming the posi- Table 1 seems to go against these global trends: quaternary
tion of the azide moiety at the tertiary position. In the cases acetate 38, obtained in low yield (Entry 12), might in fact
of regioisomeric nitriles, the shielding of the methylene car- be the result of the opening of a transient epoxide, gener-
bon atoms α to the nitrile groups observed in the 13C NMR ated by intramolecular ring opening of the azetidinium ring
spectra allowed the easy assignment of the regioisomers.
by the alkoxide.
Conclusions
In conclusion, we have demonstrated that nucleophilic
ring opening of azetidinium ions at quaternary positions
occurs readily through clean SN2 reactions and competes
efficiently with opening at primary positions. This “natural”
regioselectivity can, however, be counterbalanced when the
ideal trajectory of the attacking nucleophile is hampered by
steric crowding. Quaternary azetidinium ions thus appear
to be very interesting substrates for the synthesis of new
functionalized quaternary building blocks, and these prom-
ising results should stimulate the discovery of new synthetic
methodologies for non-racemic azetidines.
Scheme 3. Determination of the position of the azide moiety in
regioisomer 31.
Altogether, these experiments lead to the conclusion that
ring opening of azetidinium ions at the quaternary position
is intrinsically favoured. This can be explained in terms of
the weakening of the C–N bond between the quaternary
ammonium and the quaternary stereocentre due to steric
crowding. Experimentally, this weakening is apparent in the
X-ray structure of azetidinium ion 23,[14c] in which the N–
C2 bond is longer (1.57 Å) than the N–C4 bond (1.54 Å).
Simple AM1 calculations performed on model azetidinium
ions 42 and 43 (Figure 4) confirmed this observation and,
as a consequence, show a much higher positive charge on
the quaternary carbon than on the methylene in the azetidi-
nium ring.
Experimental Section
General Comments: 1H and 13C spectra were recorded with a
Bruker Avance spectrometer at 200 or 300 and 75 or 50 MHz,
respectively; chemical shifts are reported in ppm from TMS. Op-
tical rotations were determined with a Perkin–Elmer 141 instru-
ment. All reactions were carried out under argon. Column
chromatography was performed on silica gel (230–400 mesh) with
use of various mixtures of Et2O, AcOEt, PE and cyclohexane
(CyH). TLCs were run on Merck Kieselgel 60F254 plates. Melting
points are uncorrected. THF and toluene were dried with a dehy-
drating system (MB-SPS 800, Mbraun). Dichloromethane was dis-
tilled from calcium hydride. “Usual workup” means: i. decantation
of the organic layer, ii. extraction of the aqueous layer with speci-
fied solvent, iii. drying of the combined organic layers over MgSO4,
and iv. solvent evaporation under reduced pressure. Isomeric ratios
were determined by NMR analysis of crude reaction mixtures be-
fore purification. HRMS was performed with a Water Micromass
Q-Tof Micro instrument.
Synthesis of Azetidines 6 and 7
Lactone 13: Potassium carbonate (8.90 g, 64.3 mmol) and α-bromo-
butyrolactone (12, 4.12 g, 25.0 mmol) were added to a solution of
N-benzylethanolamine (4.27 g, 28.2 mmol) in acetonitrile (50 mL).
After overnight stirring, water (100 mL) was added to the reaction
mixture. Usual workup (ethyl acetate) gave a residue, which was
purified by flash chromatography (ethyl acetate). Compound 13
was obtained as a yellow oil (yield 2.52 g, 38%). Rf = 0.63 (ethyl
acetate). 1H NMR (300 MHz, CDCl3): δ = 1.62 (s, 1 H, OH), 2.16–
2.42 (m, 2 H, CH2), 2.75–2.92 (m, 2 H, CH2), 3.62 (m, 2 H,
CH2OH), 3.73–3.89 (m, 2 H, NCHHPh, NCHCO), 4.03–4.18 (m,
2 H, NCHHPh, CHHO), 3.99–4.21 (m, 1 H, CHHO) ppm. 13C
NMR (75 MHz, CDCl3): δ = 24.2, 52.7, 55.4, 58.8 (CH2), 59.1
(CH), 65.2 (CH2), 127.3, 128.4 (CH), 138.1 (CquatAr), 176.6
Figure 4. Charges and bond lengths in model azetidinium ions 42
and 43 (AM1 calculations).
It is, however, well-known that SN2 reactions are also
highly sensitive to steric crowding, and this is particularly
apparent with some of these substrates. When a conforma-
tional lock (spiroazetidinium 18), C-3 substitution of the
azetidine ring (azetidinium 22) or increased bulkiness of the
nucleophile hamper the intrinsic opening at the quaternary
(CO) ppm. IR (ATR): ν
= 3425, 3022, 2950, 2907, 2842, 1761,
˜
max
1452, 1158, 1050, 1018, 741 cm–1. HRMS (ESI, positive mode):
position due to crowding in the trajectory of the incoming calcd. for C13H18NO3 [M + H]+ 236.1287; found 236.1284.
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20890
/KAP1
Date: 05-09-12 18:42:02
Pages: 9
Regioselective Ring-Opening of Azetidinium Ions
Chloride 14: Thionyl chloride (1.42 mL, 19.6 mmol) was added to
a solution of compound 13 (2.3 g, 9.8 mmol) in dichloromethane
(50 mL). After overnight stirring, the reaction mixture was cooled
to 0 °C before addition of a saturated aqueous solution of sodium
hydrogen carbonate (100 mL). Usual workup (dichloromethane)
afforded compound 14 as an oil (yield 1.11 g, 45%). Rf = 0.86
was cooled to 0 °C before addition of a saturated aqueous solution
of sodium hydrogen carbonate (40 mL). Usual workup (dichloro-
methane) afforded compound 17 as a white solid (yield 1.63 g,
1
84%); m.p. 74 °C. Rf = 0.83 (PE/EtOAc 7:3). H NMR (300 MHz,
CDCl3): δ = 1.40 (s, 9 H, tBu), 2.85–3.00 (m, 2 H, NCH2), 3.06–
3.21 (m, 2 H, CH2O), 3.63 (d, part of AB syst., J = 13.6 Hz, 1 H,
(ethyl acetate). 1H NMR (300 MHz, CDCl3): δ = 1.62 (s, 1 H, OH), NCHHPh), 3.65 (s, 3 H, MeO), 3.76 (d, part of AB syst., J =
2.16–2.42 (m, 2 H, CH2), 2.75–2.92 (m, 2 H, CH2), 3.62 (m, 2 H,
13.6 Hz, 1 H, NCHHPh), 4.39 (s, 1 H, NHCO), 6.73–6.78 (m, 2
CH2OH), 3.73–3.89 (m, 2 H, NCHHPh, NCHCO), 4.03–4.18 (m, H, Ar), 7.16–7.28 (m, 7 H, Ar) ppm. 13C NMR (75 MHz, CDCl3):
2 H, NCHHPh, CHHO), 3.99–4.21 (m, 1 H, CHHO) ppm. 13C
NMR (75 MHz, CDCl3): δ = 24.2, 52.7, 55.4, 58.8 (CH2), 59.1
(CH), 65.2 (CH2), 127.3, 128.4 (CH), 138.1 (CquatAr), 176.6
δ = 28.2 (tBu), 42.6, 52.6 (CH2), 55.2 (CH3), 55.9 (CH2), 68.3 (CH),
81.6 (Cquat), 113.8, 127.8, 128.4, 128.8, 129.9 (CHAr), 131.3, 137.3,
158.9 (CquatAr), 171.5 (CO) ppm. IR (ATR): ν
= 2977, 2958,
˜
max
(CO) ppm. IR (ATR): ν
= 3023, 2961, 2909, 2838, 2819, 1765,
2939, 2904, 2836, 1717, 1610, 1510, 1452, 1637, 1149, 1117, 1101,
1034, 810, 749, 694 cm–1. HRMS (ESI, positive mode): calcd. for
C22H29NO3Cl [M + H]+ 390.1836; found 390.1832.
˜
max
1734, 1494, 1452, 1369, 1167, 1144, 1018, 742, 697 cm–1. HRMS
(ESI, positive mode): calcd. for C13H17NO2ClNa [M + Na]+
254.0948; found 254.0947.
Azetidine 7: A solution of NaHMDS in THF (2 m, 2.11 mL,
4.23 mmol) was added dropwise to a solution of compound 17
(1.1 g, 2.82 mmol) in THF (50 mL) cooled to 0 °C. The mixture
was allowed to warm gradually (1 h) to room temp., cooled to 0 °C
and hydrolysed by addition of a saturated aqueous solution of am-
monium chloride (40 mL). THF was evaporated and the aqueous
phase was extracted with EtOAc. Usual workup gave a residue that
was purified by flash chromatography (PE/EtOAc 97:3 to 95:5).
Compound 7 was obtained as a yellow oil (yield 601 mg, 60%). Rf
Spiroazetidine 6: A solution of 14 (1.35 g, 5.32 mmol, 80% purity)
in a mixture of THF (40 mL) and HMPA (4 mL) was cooled to
–78 °C. LiHMDS (1 m in THF, 6.6 mL, 6.6 mmol) was added drop-
wise by syringe and the mixture was gradually (1 h) warmed to
–40 °C. At this point, TLC showed consumption of the starting
material and the reaction mixture was hydrolysed at this tempera-
ture by addition of a saturated aqueous solution of NH4Cl
(10 mL). The reaction mixture, warmed to room temp., was parti-
tioned between water and EtOAc. Usual workup gave a residue
that was purified by flash chromatography (PE/EtOAc 1:1). Com-
pound 6 was obtained as an oil that crystallized on standing (yield
735 mg, 79%). Rf = 0.3 (EtOAc/PE 1:1); m.p. 82 °C. 1H NMR
(300 MHz, CDCl3): δ = 2.05–2.25 (m, 2 H, CH2), 2.21–2.48 (m, 2
H, CH2), 3.28–3.35 (m, 1 H, CHHN), 3.48–3.58 (m, 1 H, CHHN),
3.60–3.70 (m, 1 H, CHHO), 3.72 (d part of AB syst., J = 12 Hz, 1
H, NCHHAr), 3.79 (d part of AB syst., J = 12 Hz, 1 H,
NCHHAr), 3.95–4.06 (m, 1 H, CHHO), 7.19–7.35 (m, 5 H,
Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 27.6, 34.8, 49.9, 56.3,
65.3 (CH2), 68.0 (Cquat), 127.4, 128.4, 129.1 (CHAr), 137.2
1
= 0.23 (PE/Et2O 7:3). H NMR (300 MHz, CDCl3): δ = 1.55 (s, 9
H, tBu), 2.24–2.33 (m, 1 H, 3-H), 2.87–2.94 (m, 1 H, 3Ј-H), 3.19–
3.25 (m, 2 H, 4-H), 3.50 (d, part of AB syst., J = 12.7 Hz, 1 H,
NCHHPh), 3.80 (s, 3 H, MeO), 3.91 (d, part of AB syst., J =
12.7 Hz, 1 H, NCHHPh), 4.39 (s, 1 H, NHCO), 6.88 (d, J = 8.7 Hz,
2 H, Ar), 7.26–7.36 (m, 7 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 28.2 (tBu), 29.9, 49.8 (CH2), 55.3 (CH3), 56.9 (CH2),
74.9, 81.7 (Cquat), 113.7, 125.2, 126.9, 128.1, 129.7 (CHAr), 130.5,
143.1, 158.7 (CquatAr), 171.7 (CO) ppm. IR (ATR): ν
= 2969,
˜
max
2828, 1716, 1610, 1510, 1452, 1366, 1246, 1160, 1136, 1101, 1033,
810, 697 cm–1. HRMS (ESI, positive mode): calcd. for C22H28NO3
[M + H]+ 354.2069; found 354.2065.
(CquatAr), 177.3 (CO) ppm. IR (film): ν
= 1757, 1249, 1216,
˜
max
1177, 1019, 697 cm–1. HRMS (ESI, positive mode) calcd. for
General Procedure for the Synthesis of Azetidinium Ions 18–23:
Methyl trifluoromethanesulfonate (145 μL, 1.3 mmol) was added
to a solution of the required azetidine (1 mmol) in dichloromethane
(10 mL) and the mixture was stirred at room temp. for 24 h. At
this point, solvent was evaporated, and the oily residue was washed
with small portions of diethyl ether to induce crystallization. After
filtration and drying in vacuo, the following azetidinium salts were
obtained:
C13H16NO2 [M + H]+ 218.1181; found 218.1182.
β-Amino Alcohol 16: Potassium carbonate (2.9 g, 20.9 mmol), tert-
butyl 2-bromo-2-phenylacetate (4 g, 14.7 mmol) and sodium iodide
(yield 0.45 g, 3.0 mmol) were added to a solution of N-(p-meth-
oxybenzyl)ethanolamine (2.38 g, 12.7 mmol) in acetonitrile
(40 mL). After overnight stirring, the solvent was evaporated. The
residue was partitioned between water and ethyl acetate, washed
with an aqueous solution of sodium thiosulfate (5 wt.-% ) and
treated by the usual workup. After purification by flash chromatog-
raphy (PE/EtOAc 90:10), compound 16 was obtained as white crys-
Azetidinium Salt 18: White solid, yield 228 mg, quant.; m.p. 112 °C.
1H NMR showed that this compound was obtained as a 87:13 mix-
ture of diasteroisomers. The following data are for the major iso-
1
1
tals (yield 2.05 g, 44%); m.p. 84 °C. Rf = 0.65 (PE/EtOAc 6:4). H
mer: H NMR (300 MHz, CDCl3): δ = 2.65–2.90 (m, 2 H, CH2),
NMR (300 MHz, CDCl3): δ = 1.50 (s, 9 H, tBu), 2.60 (s, 1 H, OH),
2.74–2.82 (m, 1 H, NCHH), 2.90–2.98 (m, 1 H, NCHH), 3.38–3.45
(m, 1 H, CHHOH), 3.50–3.58 (m, 1 H, CHHOH), 4.03–4.18 (s, 2
H, NCH2Ph), 3.82 (s, 3 H, MeO), 4.49 (s, NHCO), 6.87–6.91 (m,
2 H, Ar), 7.25–7.39 (m, 7 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 28.1 (tBu), 52.0, 54.7 (CH2), 55.2 (CH3), 59.0 (CH2),
67.4 (CH), 81.7 (Cquat), 113.9, 127.9, 128.5, 129.0, 130.0 (CHAr),
3.36 (s, 3 H, NMe), 3.52–3.60 (m, 1 H, CH2), 3.99 (td, J = 6.3,
1.8 Hz, 1 H, NCHH), 4.31–4.48 (m, 2 H, NCHH and CHHO),
4.74 (d, part of AB syst., J = 8.3 Hz, 1 H, NCHHPh), 4.82 (d, part
of AB syst., J = 8.3 Hz, 1 H, NCHHPh), 4.82–4.95 (m, 1 H,
CHHO), 7.42–7.55 (m, 5 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 26.5, 30.2 (CH2), 45.7 (CH3), 62.1, 62.8, 65.9 (CH2),
79.7 (Cquat), 122.6 (CquatAr), 128.1 (q, J = 305 Hz, CF3), 129.7,
131.0, 136.8, 158.8 (CquatAr), 171.7 (CO) ppm. IR (ATR): ν
=
˜
max
130.9, 131.8 (CHAr), 171.8 (CO) ppm. IR (film): ν
= 3448,
˜
max
2931, 1653, 1388, 1096 cm–1. HRMS (ESI, positive mode) calcd.
for C14H18NO2 [M – TfO–]+ 232.1342; found 232.1338.
3368, 2980, 2958, 2931, 2844, 1719, 1704, 1608, 1510, 1452, 1368,
1245, 1145, 1038, 1016, 837, 810 cm–1. HRMS (ESI, positive
mode): calcd. for C22H30NO4 [M + Na]+ 372.2175; found 372.2195.
Azetidinium Salt 19: Pale yellow solid, yield 351 mg, 94%. 1H
β-Amino Chloride 17: Thionyl chloride (0.75 mL, 10.0 mmol) was NMR showed that this compound was obtained as a 75:25 mixture
1
added to a solution of compound 16 (1.85 g, 5.0 mmol) in dichloro-
methane (20 mL). After overnight stirring, the reaction mixture
of diasteroisomers. H NMR (300 MHz, CDCl3): δ = 1.47 (s, tBu,
minor isomer), 1.50 (s, tBu, major isomer), 2.54 (s, NMe, minor
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20890
/KAP1
Date: 05-09-12 18:42:02
Pages: 9
B. Drouillat, K. Wright, O. David, F. Couty
FULL PAPER
isomer), 3.23 (s, NMe, major isomer), 3.32–3.77 (m, 4 H), 3.77 (s,
OMe, major isomer), 3.82 (s, OMe, minor isomer), 4.60–4.72 (m, 2
one, only characteristic signals are detailed): δ = 0.83 (t, J = 7.0 Hz,
3 H, Me major isomer), 1.50 (t, J = 7.0 Hz, 3 H, Me minor isomer),
H), 6.82–7.89 (m, 9 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 1.72 (d, J = 6.8 Hz, 3 H, Me major isomer), 1.87 (d, J = 6.8 Hz, 3
24.4 (CH2, major isomer) and 24.5 (CH2, minor), 27.6 (tBu), 46.4
(NMe, minor isomer) and 47.9 (NMe, major isomer), 55.4 (OMe,
H, Me minor isomer), 3.40 (s, 3 H, NMe major and minor iso-
mers) ppm. The minor stereoisomer crystallized out from the mix-
ture. 13C NMR (75 MHz, [D6]acetone): δ = 14.1, 15.5 (CH3), 24.5,
38.6 (CH2), 40.0 (CH3), 62.0, 65.1 (CH), 87.1 (Cquatuat), 123.3
(CH=CH2), 128.6, 130.1, 131.7, 132.0, 132.1 (CHAr, CH=CH2),
major isomer) and 55.5 (OMe, minor isomer), 85.9 and 86.7 (Cquat
,
major isomer), 86.8 and 86.9 (Cquat, minor isomer), 114.9 (CHAr),
118.6 (CquatAr, major isomer), 123.1 (q, J = 302 Hz, CF3), 127.4
(CquatAr, major isomer), 129.5, 129.8, 130.4, 131.5, 132.3, 133.1,
134.0 (CAr), 161.3 (CO, major isomer) and 161.5 (CO, minor iso-
mer), 165.8 (CquatAr) ppm. HRMS (ESI, positive mode) calcd. for
C23H30NO3 [M – TfO–]+ 368.2226; found 368.2225.
166.9 (CO) ppm. IR (NaCl, film): ν
= 3475, 3052, 2989, 2923,
˜
max
2848, 1736, 1474, 1450, 1264, 1243, 1224, 1148, 1030, 770, 711,
635 cm–1. MS (ESI Pos): m/z = 288.3 [M – TfO–]+, 184.2, 105.0.
General Procedure for the Nucleophilic Opening of Azetidinium Ions:
A suspension of the required azetidinium triflate (1 mmol) and the
corresponding nucleophile (sodium azide, potassium cyanide, so-
1
Azetidinium Salt 20: Thick, colourless oil, yield 575 mg, 90%. H
NMR showed that this compound was obtained as a 75:25 mixture
1
of diasteroisomers. H NMR (300 MHz, CDCl3): δ = 1.27 (s, 9 H, dium or caesium acetate, 5 mmol) in DMF (5 mL) was stirred at
tBu, minor isomer), 1.51 (s, 9 H, tBu, major isomer), 2.13 (s, 3 H,
Me, minor isomer), 2.16 (s, 3 H, Me, major isomer), 2.21–2.42 (m,
1 H, 3-H), 2.90 (s, 3 H, NMe, minor isomer), 2.94 (s, NMe, major
isomer), 3.15–3.30 (m, 1 H, 3Ј-H), 3.34 (br. t, J = 8.7 Hz, 1 H, 4-
H, minor isomer), 3.55 (br. t, J = 8.7 Hz, 1 H, 4-H, major isomer),
4.04 (d, J = 12 Hz, 1 H, NCHHPh minor isomer), 4.10 (d, J =
12 Hz, 1 H, NCHHPh major isomer), 4.76 (d, J = 12 Hz, 1 H,
NCHHPh minor isomer), 4.80 (d, J = 12 Hz, 1 H, NCHHPh major
isomer), 4.85–5.01 (m, 1 H, 4Ј-H), 7.27–7.50 (m, 5 H, Ar) ppm. IR
room temp. for the time specified in Table 1. The reaction was mon-
itored by TLC until the starting azetidinium triflate had been con-
sumed. The reaction mixture was diluted with water and extracted
with Et2O. Usual workup gave a residue that was examined by
NMR and purified by flash chromatography.
Reactions with Sodium Azide
Azido Lactone 24: Clear oil (yield 100 mg, 82%). Rf = 0.32 (PE/
1
EtOAc 4:6). H NMR (300 MHz, CDCl3): δ = 1.95–2.25 (m, 4 H,
(film): ν
= 3486, 1735, 1457, 1157, 703 cm–1. HRMS calcd. for
CH2), 2.22 (s, 3 H, NMe), 2.48–2.58 (m, 2 H, CH2N) 3.50 (d, part
of AB syst., J = 13.2 Hz, 1 H, NCHHPh), 3.56 (d, part of AB syst.,
J = 13.2 Hz, 1 H, NCHHPh), 4.21–4.28 (m, 2 H, CH2O), 7.25–
7.38 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 30.4, 32.2
(CH2), 42.1 (CH3), 51.9, 62.6 (CH2), 63.9 (Cquatuat), 65.6 (CH2),
127.2, 128.3, 129.0 (CHAr), 138.4 (CquatuatAr),174.5 (CO) ppm. IR
˜
max
C17H26NO2 [M – TfO–]+ 276.1960; found 276.1964.
Azetidinium Salt 21: Sticky semi-solid, yield 694 mg, 90%. 1H
NMR showed that this compound was obtained as a 69:31 mixture
1
of diasteroisomers. H NMR (300 MHz, [D6]acetone): δ = 1.58 (s,
3 H, Me, minor isomer), 1.87 (s, 3 H, Me, major isomer), 2.25–
2.40 (m, 0.7 H, 3-H, major isomer), 2.45–2.60 (m, 0.3 H, 3-H,
minor isomer), 2.61–2.80 (m, 1 H, 3Ј-H), 2.92 (s, 0.9 H, NMe,
minor isomer), 3.01 (s, 2.1 H, NMe, major isomer), 3.45–3.60 (m,
0.3 H, 4-H, minor isomer), 3.58–3.72 (m, 0.7 H, 4-H, major iso-
mer), 3.76 (d, J = 13.5 Hz, part of AB syst., 0.7 H, major isomer),
4.01–4.42 (m, 3 H), 4.61–4.78 (m, 1 H, 4Ј-H), 4.78 (d, part of AB
syst., J = 13.5 Hz, 0.7 H), 4.93 (d, part of AB syst., J = 13.5 Hz,
0.3 H), 7.27–7.56 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3):
δ = (major isomer) = 19.8 (CH3), 25.2 (CH2), 43.9 (CH3), 59.1,
62.5, 65.1 (CH2), 85.7 (Cquat), 122.1 (q, J = 318 Hz, CF3), 129.7
(CquatAr), 130.0, 130.8, 133.2 (CHAr) ppm; δ (minor isomer) =
19.3 (CH3), 25.6 (CH2), 45.0 (CH3), 60.2, 61.4, 64.9 (CH2), 86.1
(Cquat), 122.1 (q, J = 318 Hz, CF3), 129.9 (CquatAr), 130.1, 130.9,
(film): νmax = 3348, 2101, 1768, 1601, 1024, 741 cm–1. HRMS (ESI,
˜
positive mode) calcd. for C14H19N4O2 [M + H]+ 275.1505; found
275.1508.
Azido Ester 27: Clear oil (yield 85 mg, 92%). Rf = 0.55 (PE/EtOAc
1
6:4). H NMR (300 MHz, CDCl3): δ = 1.36 (s, 9 H, tBu), 2.10 (s,
3 H, NMe), 2.15–2.35 (m, 2 H, CH2N) 3.35 (s, 2 H, NCH2Ph),
3.70 (s, 3 H, OMe) 6.75 (d, J = 9 Hz, 2 H, Ar), 7.11 (d, J = 9 Hz,
2 H, Ar), 7.25–7.32 (m, 5 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 27.8 (tBu), 35.8 (CH2), 42.1 (CH3), 52.3 (CH2), 55.2
(CH3), 61.7 (CH2), 72.0, 83.4 (Cquatuat), 113.6, 125.7, 128.3, 128.7,
130.2, 128.3 (CHAr), 130.7, 138.4, 158.6 (CquatuatAr), 169.7
(CO) ppm. HRMS (ESI, positive mode) calcd. for C23H31N4O2 [M
+ H]+ 411.2396; found 411.2396.
132.9 (CHAr) ppm. IR (film): ν
= 3432, 1452, 1243, 1158, 705,
˜
max
Azido Ester 31: Clear oil (yield 56 mg, 46%). Rf = 0.55 (PE/EtOAc
6:4). 1H NMR (300 MHz, CDCl3): δ = 1.45 (s, 9 H, tBu), 1.80–
2.01 (m, 1 H, CHHCH2N), 1.98–2.15 (m, 1 H, CHHCH2N), 2.21
(s, 3 H, NMe), 2.40–2.52 (m, 2 H, CH2N) 3.51 (br. s, 2 H,
NCH2Ph), 7.25–7.35 (m, 5 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 23.0 (CH3), 27.9 (tBu), 35.5 (CH2), 42.2 (CH3), 52.3
(CH2), 62.6 (CH2), 65.7, 82.6 (Cquatuat), 1126.1, 128.1, 129.1
697 cm–1. HRMS (ESI, positive mode) calcd. for C13H20NO [M –
TfO–]+ 206.1545; found 206.1539.
Azetidinium Salt 22: White solid, yield 90 mg, 95%; m.p. 160 °C.
Rf
=
0.50 (EtOAc/nBuOH/AcOH/H2O 1:1:1:1). 1H NMR
(300 MHz, [D6]acetone): δ = 1.67 (d, J = 6.5 Hz, 3 H, Me), 2.94
(br. d, part of AB syst., J = 12 Hz, 1 H, CHHCquat), 3.25 (br. d,
part of AB syst., J = 12 Hz, 1 H, CHHCquat), 3.47 (s, 3 H, NMe),
3.67 (s, 3 H, NMe), 4.99–5.07 (m, 3 H, CHMe, CH=CH2), 5.99–
5.64 (m, 1 H, CH=CH2), 7.39–7.49 (m, 5 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 12.9 (CH3), 34.5 (CH2), 46.4, 48.0 (CH3),
50.5, 73.4 (CH), 77.0 (Cquat), 114.5 (CN), 123.3 (CH=CH2), 128.9,
(CHAr), 138.6, (CquatuatAr), 171.2 (CO) ppm. IR (film): ν
=
˜
max
2111, 1730, 1368, 1252, 1141, 698 cm–1. HRMS (ESI, positive
mode) calcd. for C17H27N4O2 [M + H]+ 319.2132; found 319.2134.
Azido Alcohols 35 and 36: The oily residue was shown by NMR to
be an inseparable mixture of regioisomers 35 and 36 (6:4), which
were not assigned (yield 73 mg, 77%). Rf = 0.50 (PE/EtOAc 6:4).
1H NMR (300 MHz, CDCl3): δ = 1.06 (s, 3 H, Me major), 1.18 (s,
3 H, Me minor), 1.71–1.81 (m, 2 H, CH2CH2N, both regioisomers),
2.04 (s, 3 H, major NMe), 2.11 (s, 3 H, minor NMe), 2.07–2.20 (m,
2 H, CH2N, minor), 2.30–2.38 (m, 1 H, CHHN major), 2.57–2.65
(m, 1 H, CHHN major), 3.27–3.53 (m, 4 H, NCH2Ph and
130.2, 130.5 (CHAr), 130.6 (CH=CH ) ppm. IR (NaCl, film): ν
˜
2
max
= 3482, 2996, 2946, 1482, 1456, 1364, 1258, 1225, 1163, 1149, 1030,
995, 949, 755, 733, 699 cm–1. HRMS (ESI, positive mode) calcd.
for C16H21N2 [M – TfO–]+ 241.1705; found 241.1702.
Azetidinium Salt 23: Thick oil, yield 420 mg, 96%, Rf = 0.55
(dichloromethane/MeOH 90:10). This compound was obtained as
a 54:46 mixture of diastereoisomers. 1H NMR (300 MHz, [D6]acet- CH2OH), 7.17–7.28 (m, 5 H, Ar) ppm. 13C NMR (75 MHz,
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20890
/KAP1
Date: 05-09-12 18:42:02
Pages: 9
Regioselective Ring-Opening of Azetidinium Ions
CDCl3): δ = 18.4, 22.3 (CH3), 33.9 (CH2), 34.0 (CH2), 35.8 (CH2),
41.3 (CH3), 47.5, 52.7, 54.0 (CH2), 59.2 (Cquatuat), 62.6 (CH2), 64.4
(Cquatuat) 66.3, 68.0 (CH2), 126.6, 128.0, 127.7, 127.9, 128.4, 129.2
HRMS (ESI, positive mode) calcd. for C18H27N2O2 [M + H]+
303.2073; found 303.2076.
Cyano Alcohol 38: Oil (yield 62 mg, 85%). Rf = 0.7 (PE/EtOAc
(CHAr), 136.6, 139.9, (CquatAr) ppm. IR (film): νmax = 3390, 2961,
˜
1
4:6). H NMR (300 MHz, CDCl3): δ = 1.9 (s, 3 H, Me), 1.85–2.05
2089, 1141, 1255, 1048 cm–1. HRMS (ESI, positive mode) calcd.
for C13H21N4O [M + H]+ 249.1715; found 249.1717.
(m, 2 H, CH2CH2CN), 2.42 (s, 3 H, NMe), 2.11 (s, 3 H, minor
NMe), 2.48–2.65 (m, 2 H, CH2CN), 3.49–3.65 (m, 4 H, NCH2Ph
and CH2OH), 7.25–7.38 (m, 5 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 12.3 (CH2CN), 17.6 (CH3), 31.9 (CH2), 34.3 (CH3),
54.3 (CH2), 59.1 (Cquat), 66.1 (CH2), 120.5 (CN), 128.2, 128.3,
Azido Ester 40: Colourless oil (yield 92 mg, 67%). Rf = 0.60 (PE/
1
EtOAc 7:3). H NMR (300 MHz, CDCl3): δ = 1.15 (t, J = 6.7 Hz,
3 H, Me), 1.25 (d, J = 6.5 Hz, 3 H, Me), 1.73 (ddd, J = 5.3, 8.8,
14.0 Hz, 1 H, CHHCquat), 1.94 (ddd, J = 6.2, 9.2, 14 Hz, 1 H,
CHHCquat), 2.10 (s, 3 H, NMe), 2.25–2.50 (m, 4 H, 2ϫCH2), 3.46
(q, J = 6.5 Hz, 1 H, NCHMe), 4.00–4.20 (m, 2 H, CH2O), 5.02–
5.06 (m, 2 H, CH=CH2), 5.63–5.72 (m, 1 H, CH=CH2), 7.15–7.26
(m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.2, 18.8
(CH3), 29.7 (CH2), 33.7 (CH3), 41.5, 49.3, 61.7 (CH2), 63.8 (CH),
119.9 (CH=CH2), 126.9, 127.7, 128.2 (CHAr), 131.4 (CH=CH2),
128.5 (CHAr), 139.8, (CquatAr) ppm. IR (film): νmax = 3490, 2954,
˜
1734, 1370, 1233, 699 cm–1. HRMS (ESI, positive mode) calcd. for
C13H21N2O [M + H]+ 233.1654; found 233.1656.
Dienic Nitrile 39: Yellow solid (yield 15 mg, 49%). Rf = 0.25 (PE/
EtOAc 75:25). 1H NMR (300 MHz, CDCl3): δ = 0.67 (d, J =
5.4 Hz, 3 H, Me), 2.22 (s, 6 H, NMe2), 3.25–3.45 (m, 2 H, CHMe,
CHPh), 5.30–5.40 (m, 2 H, CH=CH2), 6.52 (d, J = 11 Hz, 1 H,
CH=CCN), 6.61–6.74 (m, 1 H, CH=CH2), 7.19–7.26 (m, 5 H,
Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 8.4, 39.7 (CH3), 55.3,
61.0 (CH), 117.3 (CN), 123.7 (CH=CH2), 127.4, 127.7, 129.1
(CHAr), 140.6 (CH=CCN), 143.5 (CH=CH2) ppm. IR (NaCl,
143.5 (CquatAr), 171.3 (C=O) ppm. IR (NaCl, film): ν
= 2977,
˜
max
2931, 2847, 2783, 2106, 1734, 1452, 1364, 1257, 1213, 1154, 1025,
922, 701 cm–1. HRMS (ESI, positive mode) calcd. for C18H27N4O2
[M + H]+ 331.2134; found 331.2138.
film): νmax = 2969, 2936, 2825, 2782, 2209, 1444, 1258, 1159, 1131,
˜
Reactions with Potassium Cyanide
1030, 984, 928, 796 cm–1. HRMS (ESI, positive mode) calcd. for
C16H21N2 [M + H]+ 241.1705; found 241.1706.
Cyano Lactone 25: White solid (yield 112 mg, 72%); m.p. 88 °C. 1H
NMR (300 MHz, CDCl3): δ = 1.90–2.25 (m, 4 H, CH2), 2.05 (s, 3
H, NMe), 2.48–2.68 (m, 2 H, CH2N) 3.42 (d, part of AB syst., J
= 13.5 Hz, 1 H, NCHHPh), 3.49 (d, part of AB syst., J = 13.2 Hz,
1 H, NCHHPh), 4.11–4.23 (m, 1 H, CHHO), 4.35 (td, J = 9, 3 Hz,
1 H, CHHO), 7.19–7.26 (m, 5 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 11.2, 28.1, 30.2 (CH2), 35.1 (CH3), 56.0, 65.1 (CH2),
70.3 (Cquat), 119.7 (CN), 127.4 (CquatAr), 128.4, 128.5 (CHAr),
Reactions with Sodium or Caesium Acetate
Aminocyclopentenone 26: Clear oil (yield 40 mg, 39%). Rf = 0.25
(EtOAc). 1H NMR (300 MHz, CDCl3): δ = 2.17 (s, 3 H, NMe),
2.40–2.45 (m, 2 H, CH2CH2N), 2.55–2.61 (m, 2 H, CH2CH2N),
3.45 (s, 2 H, NCH2Ph), 4.69 (d, J = 1.5 Hz, 2 H, CH2O), 7.07 (t,
J = 1.5 Hz, 1 H, C=CH), 7.19–7.27 (m, 5 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 20.8 (CH2), 42.0 (NMe), 54.7, 62.4, 70.3
(CH2), 127.1, 128.3, 129.0 (CHAr), 132.4, 138.8 (Cquat), 145.2
138.2 (CquatAr) 175.9 (CO) ppm. IR (film): ν
= 2795, 2236,
˜
max
1762, 1164, 698 cm–1. HRMS (ESI, positive mode) calcd. for
C15H19N2O2 [M + H]+ 259.1447; found 259.1444.
(CH), 174.5 (CO) ppm. IR (film): ν
= 2934, 2784, 1747, 1452,
˜
max
739, 699 cm–1. HRMS (ESI, positive mode) calcd. for C14H18NO2
Cyano Esters 28 and 29: Oil. Inseparable mixture (76:24) of re-
gioisomers 28 and 29 (yield 53 mg, 64%). Rf = 0.55 (PE/EtOAc
[M + H]+ 232.1338; found 232.1336.
1
Amino Ester 30: Oil (yield 33 mg, 39%). Rf = 0.5 (PE/EtOAc 9:1).
1H NMR (300 MHz, CDCl3): δ = 1.51 (s, 9 H, tBu), 1.84 (s, 3 H,
MeCO), 2.19 (s, 3 H, NMe), 2.32–2.37 (m, 2 H, CH2Cquat), 3.45
(d, J = 15 Hz, 1 H, NCHHAr), 3.67 (d, J = 15 Hz, 1 H, NCHHAr),
3.73 (s, 3 H, OMe), 3.81–3.86 (m, 2 H, CH2O), 6.80 (d, J = 8 Hz,
2 H, CHAr), 7.16–7.26, (m, 5 H, Ar), 7.36 (d, J = 8 Hz, 2 H,
CHAr) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.9, 28.5, 35.9
(CH3), 37.2 (CH2), 55.3 (CH3), 56.2, 61.4 (CH2), 72.9, 82.1 (Cquat),
113.7, 127.3, 128.6, 128.8 (CHAr), 132.4, 140.6, 158.9, (CquatAr),
6:4). H NMR (300 MHz, CDCl3): δ = 1.29 (s, 9 H, tBu, major),
1.59 (s, 9 H, tBu, minor), 2.07 (s, 3 H, NMe, major), 2.19 (s, 3 H,
NMe, minor), 2.08–2.18 (m, 2 H), 2.31–2.45 (m, 2 H), 2.55–2.66
(m, 2 H), 3.71 (s, 3 H, OMe, major), 3.73 (s, 3 H, OMe, minor),
6.74–7.48 (m, 9 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ =
major isomer 28 = 27.5 (tBu), 35.2 (CH2), 41.6 (CH3), 52.3 (CH2),
53.4 (Cquat), 55.3 (CH3), 62.0 (CH2), 84.1 (Cquat), 113.5 (CHAr),
118.6 (CN), 125.7, 128.3, 128.7, 130.2, (CHAr), 130.5, 138.2, 158.6
(CquatAr), 166.2 (CO) ppm; δ minor isomer 29 = 12.8 (CH2), 28.5
(tBu), 34.8 (CH2), 42.2 (CH3), 73.5 (Cquat), 55.3 (CH3), 59.4 (CH2),
73.5 (Cquat), 113.8 (CHAr), 119.9 (CN), 127.2, 128.4, 128.8, 130.3,
(CHAr), 130.6, 139.5, 158.7 (CquatAr), 166.2 (CO) ppm. IR (film):
170.8, 171.0 (C=O) ppm. IR (film): νmax = 2973, 2830, 1735, 1715,
˜
1510, 701 cm–1. HRMS (ESI, positive mode) calcd. for C25H34NO5
[M + H]+ 428.2437; found 428.2434.
ν
= 2981, 2240, 1734, 1510, 1243, 697 cm–1. HRMS (ESI, posi-
˜
max
Amino Ester 34: Colourless oil (yield 39 mg, 8%). Rf = 0.43 (PE/
EtOAc 9:1). 1H NMR (300 MHz, CDCl3): δ = 1.32 (br. s, 3 H, Me),
1.44 (s, 9 H, tBu), 1.90–2.20 (br. m, 2 H, CH2), 1.96 (s, 3 H,
MeCO), 2.12 (br. s, 3 H, NMe), 3.48–3.65 (br. m, 2 H, CH2Ar),
4.20 (t, J = 7.6 Hz, 2 H, CH2O), 7.15–7.26, (m, 5 H, Ar) ppm. 13C
NMR (75 MHz, CDCl3): δ = 20.6, 21.0, 28.2, 35.2 (CH3), 35.0,
56.8, 61.1 (CH2), 128.3 (CHAr), 171.1 (C=O) ppm. Other carbon
tive mode) calcd. for C24H31N2O3 [M + H]+ 395.2338; found
395.2335.
Cyano Esters 32 and 33: Oil. Inseparable mixture (25:75) of re-
gioisomers 32 and 33 (yield 56 mg, 61%). 1H NMR (300 MHz,
CDCl3): δ = 1.32 (br. s, 3 H, Me), 1.50 (br. s, 9 H, tBu), 1.92–2.38
(m, 5 H, CH2CH2N and NMe), 2.35–2.75 (m, 2 H, CH2N), 3.50–
3.85 (m, 2 H, NCH2Ph), 7.285–7.37 (m, 5 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ (major isomer 33) = 12.8 (CH2), 29.5 (tBu),
36.2 (CH2), 36.9 (CH3), 43.0 (CH3), 62.6 (CH2), 65.9 (Cquat), 82.8
(Cquat), 121.5 (CN), 129.1, 129.7, 128.0, (CHAr), 141.2 (CquatAr),
174.0 (CO) ppm; δ (minor isomer 32) = 29.3 (tBu), 31.0 (CH3), 33.3
signals broadened. IR (NaCl, film): νmax = 2976, 2931, 2798, 1738,
˜
1719, 1453, 1366, 1230, 1143, 1126, 1108, 1028, 847, 733, 698 cm–1.
HRMS (ESI, positive mode) calcd. for C19H30NO4 [M + H]+
336.2175; found 336.2177.
Amino Ester 38: Oil (yield 40 mg, 17%). Rf = 0.3 (EtOAc). 1H
(CH2), 42.4 (Cquat), 42.9 (CH3), 53.0 (CH2), 63.6 (CH2), 123.4 NMR (300 MHz, CDCl3): δ = 1.15 (s, 3 H, Me), 1.84 (s, 3 H,
(CN), 128.2, 129.3, 129.4, 1 (CHAr), 139.6 (CquatAr), 174.0 MeCO), 1.52–1.65 (m, 1 H, CHHCH2N), 1.71–1.95 (m, 1 H,
(CO) ppm. IR (film): νmax = 2973, 2244, 1717, 1367, 733, 698 cm–1. CHHCH2N), 2.08 (s, 3 H, NMe or CH3CO), 2.25 (s, 3 H, NMe or
˜
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20890
/KAP1
Date: 05-09-12 18:42:02
Pages: 9
B. Drouillat, K. Wright, O. David, F. Couty
FULL PAPER
Y. Tezuka, Macromol. Chem. Phys. 2000, 201, 1673–1678; f) S.
Kenis, M. D’hoogue, G. Verniest, T. A. D. Thi, C. P. The, T. V.
Nguyen, N. De Kimpe, J. Org. Chem. 2012, 77, 5982–5992.
[3] a) V. R. Gaertner, Tetrahedron Lett. 1967, 4, 343–347; b) V. R.
Gaertner, J. Org. Chem. 1968, 33, 523–530; c) N. J. Leonard,
D. A. Durand, J. Org. Chem. 1968, 33, 1322–1333; d) M. K.
Gorai, D. Shukla, A. Bhattacharyya, J. Org. Chem. 2012, 77,
3740–3753; e) M. K. Ghorai, D. Shukla, K. Das, J. Org. Chem.
2009, 74, 7013–7022; f) M. K. Ghorai, K. Das, A. Kumar, Tet-
rahedron Lett. 2007, 48, 4373–4377.
[4] a) R. H. Higgins, W. J. Faircloth, R. G. Baughman, Q. L. Ea-
ton, J. Org. Chem. 1994, 59, 2172–2178; b) P. O’Brien, D. W.
Phillips, T. D. Towers, Tetrahedron Lett. 2002, 43, 7333–7335.
[5] a) A. Sudo, Y. Iitaka, T. Endo, J. Polym. Sci., Part A 2002,
40, 1912–1917; b) F. Couty, O. David, F. Durrat, G. Evano, S.
Lakdhar, J. Marrot, M. Vargas-Sanchez, Eur. J. Org. Chem.
2006, 3479–3490.
CH3CO), 2.70–2.80 (m, 2 H, CH2N), 3.55 (s, 2 H, CH2OH), 3.86
(d, J = 11 Hz, part of AB syst., 1 H, NCHHPh), 3.95 (d, J = 11 Hz,
part of AB syst., 1 H, NCHHPh), 7.18–7.45 (m, 5 H, CHAr) ppm.
13C NMR (75 MHz, CDCl3): δ = 21.0, 25.2 (CH3), 32.3 (CH2),
41.6 (NMe), 53.4, 62.7, 70.6 (CH2), 72.0 (Cquat), 127.6, 128.5, 129.4
(CHAr), 137.3 (CquatAr), 171.0 (C=O) ppm. IR (film): νmax = 2954,
˜
1734, 1370, 1233, 1039 cm–1. HRMS (ESI, positive mode) calcd.
for C15H24NO3 [M + H]+ 266.1756; found 256.1757.
Amino Ester 41: PPh3 (yield 68 mg, 0.258 mmol) was added to a
solution of 31 (75 mg, 0.235 mmol) in THF (3 mL) and the solu-
tion was heated at reflux for 12 h. Water (0.3 mL) was then added
and the mixture was again heated at reflux for 5 h. The reaction
mixture was then allowed to cool to room temp. and partitioned
between water and diethyl ether. Usual workup gave a residue
(127 mg), which was dissolved in dichloromethane (4 mL). Ac2O
(0.12 mL), triethylamine (50 mL) and DMAP (10 mg) were added,
and the mixture was stirred at room temp. for 5 h. After addition
of water and EtOAc, usual workup gave an oil that was purified
by flash chromatography (EtOAc). The title compound was ob-
tained as a clear oil (15 mg, 20%). Rf = 0.5 (40% aq. NH3/EtOAc
2:98). 1H NMR (300 MHz, CDCl3): δ = 1.37 (s, 9 H, tBu), 1.45 (s,
3 H, Me), 1.78 (s, 3 H, Me) 1.85–1.98 (m, 1 H, CHHCH2N), 2.05–
2.15 (m, 1 H, CHHCH2N), 2.16 (s, 3 H, NMe), 2.28–2.48 (m, 2 H,
CH2N), 3.35 (d, part of an AB syst., J = 12 Hz, 1 H, NCHHPh),
3.49 (d, part of an AB syst., J = 12 Hz, 1 H, NCHHPh), 7.15–7.30
(m, 5 H, Ar), 7.61 (br. s, 1 H, NH) ppm. HRMS (ESI, positive
mode) calcd. for C19H31N2O3 [M + H]+ 335.2335; found 335.2334.
[6] a) Y. Hata, M. Watanabe, Tetrahedron 1987, 43, 3881–3888; b)
A. Jeziorna, J. Helin´ski, B. Krawiecka, Synthesis 2003, 2, 288–
294.
[7]
a) J. Helin´ski, Z. Skrzypczyn´ski, J. Michalski, Tetrahedron Lett.
1995, 36, 9201–9204; b) A. Bakalarz, J. Helin´ski, B. Krawiecka,
J. Michalski, M. J. Potrzebowski, Tetrahedron 1999, 55, 12211–
12226; c) A. Bakalarz-Jeziorna, J. Helin´ski, B. Krawiecka, J.
Chem. Soc. Perkin Trans. 1 2001, 1086–1090; d) A. Jeziorna, J.
Helin´ski, B. Krawiecka, Tetrahedron Lett. 2003, 44, 3239–3243;
e) B. Krawiecka, A. Jeziorna, Tetrahedron Lett. 2005, 46, 4381–
4384.
[8]
a) J. M. Concellο´n, E. Riego, P. L. Bernad, Org. Lett. 2002, 4,
1303–1305; b) M.-B. Giudicelli, D. Picq, D. Anker, Tetrahedron
1992, 48, 6033–6042; c) D. S. Coffey, A. I. McDonald, L. E.
Overman, J. Org. Chem. 1999, 64, 8741–8742; d) M. K. Gho-
rai, D. P. Tiwar, A. Kumar, K. Das, J. Chem. Sci. 2011, 123,
951–961; e) M. K. Ghorai, A. Kumar, D. P. Tiwari, J. Org.
Chem. 2010, 75, 137–151; f) M. K. Ghorai, K. Das, A. Kumar,
A. Das, Tetrahedron Lett. 2006, 47, 5393–5397; g) B. Alcaide,
P. Almendros, C. Aragoncillo, N. R. Salgado, J. Org. Chem.
1999, 64, 9596–9604.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H NMR and 13C NMR for new azetidines 6–7,
azetidinium ions 18–19, ring-opened compounds 24–27, 30–31, 37–
38 and 40–41.
Acknowledgments
[9]
F. Couty, O. David, F. Durrat, Tetrahedron Lett. 2007, 48,
1027–1031.
The University of Versailles St-Quentin en Yvelines and the Centre
National de la Recherche Scientifique (CNRS) are acknowledged
for financial support.
[10] F. Couty, O. David, B. Drouillat, Tetrahedron Lett. 2007, 48,
9180–9184.
[11] F. Couty, G. Evano, Synlett 2009, 3053–3064, and references
cited therein.
[1] N. De Rycke, O. David, F. Couty, Org. Lett. 2011, 13, 1836–
1839. For recent examples of regioselective opening of aziridin-
ium ions, see: a) S. Catak, M. D’hoogue, N. De Kimpe, M.
Waroquier, V. Van Speybroeck, J. Org. Chem. 2010, 75, 885–
896; b) S. Stankovic, H. Goossens, S. Catak, M. Tezcan, M.
Waroquier, V. Van Speybroeck, M. D’hoogue, N. De Kimpe, J.
Org. Chem. 2012, 77, 3181–3190; c) S. Kenis, M. D’hoogue, G.
Verniest, V. D. Nguyen, T. A. D. Thi, T. V. Nguyen, N.
De Kimpe, Org. Biomol. Chem. 2011, 9, 7217–7223.
[2] a) J. M. Concellο´n, P. L. Bernad, J. A. Pérez-Andrés, Tetrahe-
dron Lett. 2000, 41, 1231–1234; b) F. Couty, F. Durrat, G. Ev-
ano, Synlett 2005, 1666–1670; c) S. Bernstein, M. Heller, J. Org.
Chem. 1971, 36, 1386–1389; d) J. Szmuszkovicz, M. P. Kane, J.
Org. Chem. 1981, 46, 3728–3730; e) H. Oike, M. Washizuka,
[12] M. Sivaprakasam, F. Couty, O. David, J. Marrot, R. Sridhar,
B. Srinivas, K. Rama Rao, Eur. J. Org. Chem. 2007, 5734–5739.
[13] D.-H. Leng, D.-X. Wang, J. Pan, Z.-T. Huang, M.-X. Wang, J.
Org. Chem. 2009, 74, 6077–6082.
[14] a) C. Cativiela, D. Díaz-de-Villegas, Tetrahedron: Asymmetry
2000, 11, 645–732; b) T. Kawabata, S. Matsuda, S. Kawakami,
D. Monguchi, K. Moriyama, J. Am. Chem. Soc. 2006, 128,
15394–15395; c) B. Drouillat, F. Couty, J. Marrot, Synlett 2009,
5, 767–770; d) C. Cativiela, M. Ordoñez, Tetrahedron: Asym-
metry 2009, 20, 1–63.
[15] F. Couty, B. Drouillat, F. Lemée, Eur. J. Org. Chem. 2011, 794–
801..
Received: July 5, 2012
Published Online: ᭿
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20890
/KAP1
Date: 05-09-12 18:42:02
Pages: 9
Regioselective Ring-Opening of Azetidinium Ions
Azetidinium Ring Opening
Dissymmetric azetidinium ions with sec-
ondary and quaternary carbon atoms α to
the nitrogen atoms were treated with cyan-
ide, azide and acetate anions. The regiose-
lectivity of the ring opening tends to favour
opening at the quaternary carbon, but
these reactions are highly sensitive to steric
hindrance. Complete inversion at the quat-
ernary centres demonstrates that clean SN2
reactions operate.
B. Drouillat, K. Wright, O. David,
F. Couty* .......................................... 1–9
Insight into the Regioselectivity of Nucleo-
philic Ring-Opening of Azetidinium Ions
Containing Quaternary Carbon Atoms
Keywords: Nitrogen heterocycles / Small
ring systems / Nucleophilic substitution /
Regioselectivity / Reaction mechanisms
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9