Experimental and theoretical investigations for the regio and stereoselective transformation of trans 1,2,3-trisubstituted aziridines into trans oxazolidin-2-ones

Article abstract of DOI:10.1016/S0040-4020(02)01565-X

The regio and stereoselective transformation of trans 1,2,3-trisubstituted aziridines into trans oxazolidin-2-ones takes place in good yield. However, the cis configuration at C2 and C3 in monocyclic aziridines is a limiting factor for this transformation

Full text of DOI:10.1016/S0040-4020(02)01565-X

Tetrahedron 59 (2003) 677–683
Experimental and theoretical investigations for the regio
and stereoselective transformation of trans 1,2,3-trisubstituted
aziridines into trans oxazolidin-2-ones
†
a
Luisa Testa,a Mohamed Akssira,a Elena Zaballos-Garcıa, Pau Arroyo,a b Luis R. Domingoa b
,
,
, ,
*
´
and Jose Sepulveda-Arques
a
*
´
a
´
´
Departamento de Quımica Organica, Universidad de Valencia, Dr. Moliner 50, E-46100 Burjassot, Valencia, Spain
bInstituto de Ciencia Molecular, Universidad de Valencia, Valencia, Spain
Received 25 July 2002; revised 17 October 2002; accepted 26 November 2002
Abstract—The regio and stereoselective transformation of trans 1,2,3-trisubstituted aziridines into trans oxazolidin-2-ones takes place in
good yield. However, the cis configuration at C2 and C3 in monocyclic aziridines is a limiting factor for this transformation. Ab initio
calculations show that while the ring-opening process assisted by iodide is regioselective, the subsequent ring-closure is responsible for the
retention of the configuration at the trans oxazolidin-2-one. The larger energy found for the ring-closure process for the cis aziridines
accounts for the non-formation of the cis oxazolidin-2-ones. q 2003 Elsevier Science Ltd. All rights reserved.
The reaction of N-alkylaziridines 1 with di-tert-butyl
dicarbonate (Boc2O) and sodium iodide in acetone was
previously reported as a new synthetic procedure for the
stereoselective preparation of oxazolidin-2-ones 2 (see
Scheme 1).1 Further work on this topic has shown that the
cis configuration of C2 and C3 in 1,2,3-trisubstituted
monocyclic aziridines is a limiting factor for the trans-
formation of 1 into 2. The substrates used for this study were
the trans aziridines 1a,b and the cis aziridines 1c,d. They
were prepared from (1R,2S) (2)-ephedrine (3a), (1S,2S)
(þ)-pseudoephedrine (4a), and the racemic 3-methylamino-
2-butanols2 5b and 6b (see Scheme 2).
The reaction of 3a with triphenylphosphine–diethyl azodi-
carboxylate yielded trans (1S,2S)-1,2-dimethyl-3-phenyl-
aziridine (1a),3 and the reaction of 3a with thionyl chloride–
sodium hydroxide gave cis (1S,2R)-1,2-dimethyl-3-phenyl-
aziridine (1c). The trans aziridine 1a was converted into the
trans oxazolidin-2-one4 2a in 84% yield, by reaction with
di-tert-butyl dicarbonate and sodium iodide in acetone at
room temperature. However, when a similar transformation
was attempted on the cis aziridine 1c, the expected cis
oxazolidin-2-one 2c was not detected in the crude mixture.
The aziridines 1a and 1c were also prepared using (1S,2S)
(þ)-pseudoephedrine 4a as starting material (see Scheme
2). The trans aziridine 1a was obtained with thionyl
chloride–sodium hydroxide, while the cis aziridine 1c was
prepared with triphenylphosphine–diethyl azodicarboxyl-
ate. The trans aziridine 1a was then transformed into the
oxazolidin-2-one 2a in 72% yield, by reaction with di-tert-
butyl dicarbonate and sodium iodide in acetone at room
temperature. However, the cis aziridine 1c did not afford
the cis oxazolidin-2-one 2c, under the same reaction
conditions.
Scheme 1. R¼3-oxocyclohexyl or 3-oxocyclobutyl, R1¼R2¼R3¼R4¼H;
R¼3-oxocyclohexyl or 3-oxocyclobutyl, R1¼R3¼R4¼H, R2¼CH3; R¼3-
oxocyclohexyl or 3-oxocyclobutyl R1¼R4¼H, R2¼R3¼(CH2)3; R¼3-
oxocyclohexyl or benzyl, R1¼R4¼H, R2¼R3¼(CH2)4; R¼methyl, R1¼H,
R2¼C6H5, R3¼H, R4¼CH2OTBDMS.
To verify the influence of the relative configuration of the
C2 and C3 carbon atoms of the trisubstituted aziridines, two
new derivatives, 1b and 1d, were prepared (see Scheme 2).
These aziridines were obtained from racemic (2R,3S) and
(2S,3R) 3-methylamino-2-butanol (5b) as starting material.2
The reaction of 5b with triphenylphosphine–diethyl
azodicarboxylate yielded the trans aziridine 1b, while the
reaction with thionyl chloride–sodium hydroxide gave the
cis aziridine 1d.
Keywords: aziridines; oxazolidinones; regioselectivity; stereoselectivity;
molecular mechanism; ab initio calculations.
*
Corresponding authors. Fax: þ34-96-354-3152;
e-mail: domingo@utopia.uv.es, jose.sepulveda@uv.es.
On leave from the Universite Hassan II Mohammedia, Marocco.
†
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01565-X

678
L. Testa et al. / Tetrahedron 59 (2003) 677–683
Scheme 2. (i) Ph3P/DEAD; (ii) SOCl2/NaOH; (iii) (Boc)2O/INA, acetone.
The transformation of the trans aziridine 1b into the trans
oxazolidin-2-one 2b took place by reaction with di-tert-
butyl dicarbonate and sodium iodide in acetone at room
temperature in 80% yield. However, the cis aziridine 1d
under the same reaction conditions did not afford the cis
oxazolidin-2-one 2d. The aziridines 1b and 1d were also
prepared from racemic (2R,3R) and (2S,3S) 3-methylamino-
2-butanol (6b). In this case the trans aziridine 1b prepared
with thionyl chloride–sodium hydroxide was converted into
the trans oxazolidin-2-one 2b in 75% yield. However, when
the cis aziridine 1d obtained by reaction of 6b with
triphenylphosphine–diethyl azodicarboxylate was reacted
with di-tert-butyl dicarbonate and sodium iodide in acetone,
only a complex mixture was obtained, but the cis
oxazolidin-2-one 2d was not detected.
formation of an aziridinium cation intermediate 7. The ring-
opening of the aziridinium 7 promoted by the nucleophilic
attack of the iodide anion to the C2 carbon atom affords the
urethane iodide 8. The subsequent displacement of iodide in
compound 8 through the intramolecular nucleophilic attack
of the carbonyl oxygen atom of the urethane framework of 7
affords the cationic O-alkylated oxazolidin-2-one inter-
mediate 9. This intermediate yields the final trans
oxazolidin-2-ones 2a and 2b through the extrusion of the
tert-butyl group (see Scheme 3).
At this stepwise mechanism, while the second step is
responsible for the regioselectivity observed at the trans
aziridine 1a, the formation of the iodide intermediates 8 and
the subsequent intramolecular displacement of iodide are
responsible for the observed retention of the C2 configu-
ration on the trans oxazolidin-2-ones 2a and 2b. The
formation of the intermediate 8 could take place also
through a stepwise process in which the ring-opening of
the aziridinium intermediate 7 could be done without the
participation of the iodide anion to give a carbocationic
intermediate. However, this path was discarded because of
the stereospecificity of the reaction excludes the formation
of a planar carbocation, and the fact that when the reaction
was made experimentally in presence of chloride instead of
iodide the formation of the oxazolidin-2-ones did not take
place.1
1. Theoretical studies on the mechanism
In order to explain the unlike behaviour of the trans and cis
1,2,3-trisubstituted aziridines 1a–d a theoretical study was
carried out. For the stereoselective conversion of the trans
trisubstituted aziridines 1a and 1b into the trans oxazolidin-
2-ones 2a and 2b, respectively, a stepwise mechanism was
proposed (see Scheme 3). The first step is the nucleophilic
attack of the nitrogen atom of the trans aziridines 1a and
1b to a carbonyl group of di-tert-butyl dicarbonate with
Scheme 3.

L. Testa et al. / Tetrahedron 59 (2003) 677–683
679
Scheme 4.
In order to give light for the proposed mechanism, the steps
II and III, which are responsible for the regio and trans
stereoselection, were theoretically studied. A preliminary
AM1 semi-empirical5 study of the potential energy surface
(PES) for complete models that included the bulky Boc
framework and the iodide anion allowed to locate the
corresponding intermediates 7–9. However, all attempts to
locate the corresponding transition structures (TS) at this
semi-empirical level were unsuccessful. Therefore, ab initio
calculations at the HF/6-31Gp6 computational level were
necessary in order to perform a complete characterization of
the PES. A reduced model where the bulky tert-butyl group
of the Boc was replaced by a methyl group and the iodine
atom by the chlorine atom was used in order to do feasible
the ab initio calculations. A schematic representation of the
steps II and III, including the atom numbering, for the trans
3-methyl-2-phenylaziridine is given in Scheme 4, while
the total and relative energies are in Table 1. In Figure 1 the
energy profiles for the stationary points corresponding to
the ring-opening and ring-closure steps for the cis and trans
aziridines are shown. The geometries of the TSs are
displayed in Figure 2.
Table 1. HF/6-31Gp total energies (au) and SCRF relative energies
(kcal/mol, in parentheses, 1¼20.7) for the stationary points corresponding
to the ring-opening and ring-closure steps for the aziridinium intermediates
IN1-t and IN1-c
The step II is the ring-opening of the aziridinium
intermediate IN1-t to give the corresponding urethane
chloride IN2-2t, while the step III corresponds with the
ring-closure of IN2-2t to give the cationic O-alkylated
oxazolidin-2-one intermediate IN3-2t. For the ring-opening
process two regioisomeric path are possible depending on
the nucleophilic attack of the chloride anion to the C2 or C3
carbon atoms of the aziridinium intermediate IN1-t (see
Scheme 4). Due to the ionic character of some species, the
relative energies were obtained in acetone (see Section 3.1).
The ring-opening process is thermodynamically very
favourable, ca. 231 kcal/mol, because of the formation of
the neutral urethane chlorides IN2-2t and IN2-3t. In
addition, this step presents a very low activation barrier.
The relative energies of TS1-2t and TS1-3t relative to the
aziridinium intermediate IN1-t plus chloride anion are 0.8
In vacuo
In acetone
trans Aziridines
IN1-t
TS1-2t
TS1-3t
IN2-2t
IN2-3t
TS2-2t
IN3-2t
2667.678662
21127.334849
21127.331575
21127.417058
21127.414800
21127.359572
21127.396539
2667.739785
21127.370939
21127.364290
21127.422165
21127.420780
21127.386235
21127.415944
(0.8)
(5.0)
(231.3)
(230.5)
(28.8)
(227.4)
cis Aziridines
IN1-c
TS1-2c
IN2-2c
TS2-2c
IN3-2c
2667.670849
21127.330453
21127.414800
21127.354008
21127.394177
2667.733198
21127.364600
21127.420799
21127.375799
21127.414038
(0.7)
(234.6)
(26.4)
(230.4)
Relative to IN1-tþCl2 or IN1-cþCl2. The total energy of Cl2 in acetone is
2459.632432 a.u.
Figure 1. Energy profiles (in kcal/mol, acetone) for the stationary points corresponding to the ring-opening and ring-closure steps for the aziridinium
intermediates IN1-t and IN1-c.

680
L. Testa et al. / Tetrahedron 59 (2003) 677–683
Figure 2. Transition structures corresponding to the ring-opening, TS1-2t and TS1-3t, and ring-closure, TS2-2t, steps for the trans aziridinium intermediate
IN1-t. The values of the bond lengths directly involved in the process are given in angstroms.
and 5.0 kcal/mol, respectively. In consequence, in acetone
TS1-2t is 4.2 kcal/mol less energetic than TS1-3t. This
energetic result, which is in reasonable agreement with
the experiments, allows us to explain the formation of the
5-phenyl-oxazolidin-2-one 2a. Therefore, the larger stabili-
zation of the TS corresponding to the nucleophilic attack of
the chloride anion to the benzylic C2 position of aziri-
dinium intermediate IN1-t accounts for the observed
regioselectivity.
the cationic O-alkylated oxazolidin-2-one intermediate
IN3-2t accounts for the large stability of this intermediate
(see IN3-2t in Scheme 4); IN3-2t is 27.4 kcal/mol less
energetic than the isomeric aziridinium IN1-t (see Fig. 1).
In order to explain the unlike reactivity of the trans and cis
1,2,3-trisubstituted aziridines, the ring-opening and ring-
closure steps for the cis aziridinium intermediate IN1-c
were also studied (see Scheme 5). Assuming a similar
regioselectivity than that observed at the trans aziridinium
IN1-t, we considered only the attack of the chloride anion to
the benzylic C2 position of IN1-c. The barrier for this
nucleophilic attack via TS1-c2 is 0.7 kcal/mol. Therefore,
this barrier is similar to that found for the ring-opening of
the trans aziridinium intermediate IN1-t via TS1-2c. These
results are in agreement with the disappearing of both
trans and cis disubstituted aziridines at the experimental
conditions. However, a different result was found for the
ring-closure step. The activation energy for this step via
TS2-2c is 28.2 kcal/mol. Therefore, this barrier is 5.7 kcal/
mol larger than that found for the trans isomer via TS2-2t.
These energetic results allow us to explain the unlike
The step III corresponds with the formation of the
oxazolidin-2-one ring through the internal nucleophilic
attack of the carbonylic oxygen atom of the urethane to the
chloride substituted C2 carbon atom of IN2-2t. Due to the
large regioselectivity found at the step II, the ring-closure
for the intermediate IN2-3t was not studied. The activation
energy for the ring-closure via TS2-2t is 22.5 kcal/mol.
Although the process is slightly endothermic, 2.9 kcal/mol,
the subsequent extrusion of the tert-butyl cation framework
on 9, and its posterior conversion in isopropene turn on this
step as irreversible. The presence of one a nitrogen atom
and two a oxygen atoms at the carbocationic C4 center of
Scheme 5.

L. Testa et al. / Tetrahedron 59 (2003) 677–683
681
˚
and 2.789 and 1.751 A at TS1-2c, respectively (see Fig. 2).
A similar lengths are found at the reaction of the cis isomer
˚
IN1-c, 2.846 and 1.734 A at TS1-2c, respectively (see
Fig. 3). For the TSs associated with the ring-closure
processes, the lengths of the O–C forming bond and
˚
Cl–C breaking bond are 1.853 and 2.743 A at TS2-2t, and
˚
1.994 and 2.706 A at TS2-2c, respectively. These lengths
indicate that for the ring-closure processes the more
favourable trans reactive channel is more advanced.
A conformational analysis along the C2–C3 bond for
the TSs associated with the ring-closure step, TS2-2t and
TS2-2c, shows that whereas the former has the C2 phenyl
and C3 methyl substituents in an anti arrangement in the
latter these substituents are in an eclipsed arrangement (see
Fig. 4). Therefore, the hindrance that appears between the
methyl and phenyl substituents at the eclipsed arrangement,
is responsible for the larger energy of TS2-2c; the cis
TS2-2c is ca. 6.2 kcal/mol more energetic than trans
TS2-2t. In consequence, intermediates as IN2-2c can try
other competitive intermolecular nucleophilic substitutions
of iodide, for instance the attack of the BocO2 anion
generated in the first step, allowing to explain the non-
formation of the cis oxazolidin-2-one intermediate IN3-2c.
However, the presence of the 5 or 6-membered-ring at the
cis bicyclic aziridines prevents the C2–C3 bond-rotation
allowing, in consequence, the formation of the cis bicyclic
oxazolidin-2-ones by an intramolecular iodide displacement
(see TS2-BC in Fig. 4).1,7
Figure 3. Transition structures corresponding to the ring-opening, TS1-2c,
and ring-closure, TS2-2c, steps for the cis aziridinium intermediate IN1-c.
The values of the bond lengths directly involved in the process are given in
angstroms.
The values of the unique imaginary frequency of the TSs
associated with the ring-opening process are 334 cm21 at
TS1-2t, 366 cm21 at TS1-3t and 307 cm21 at TS1-2c;
while these values for the TSs associated with the ring-
closure are 402 cm21 at TS2-2t and 324 cm21 at TS2-2c.
Analysis of the atomic motion along these vibrational
frequencies indicates that these TSs are mainly associated
with the motion of the N and C atoms along the C–N bond-
breaking for the TSs associated with the step II, and the C
and O atoms along the C–O bond-formation for the TSs
associated with the step III; the motion of the Cl atom is
negligible at these TSs.
reactivity for the trans and cis 1,2,3-trisubstituted aziridines.
While the trans aziridines 1a and 1b afford directly the trans
oxazolidin-2-one 2a and 2b through an intramolecular
iodide displacement, for the cis aziridines 1c and 1d other
competitive channels associated with the intermolecular
substitution of iodide can be operative as a consequence of
the large energy for the intramolecular ring-closure.
For the TSs associated with the ring-opening process of
the trans aziridinium IN1-t the lengths of the Cl–C forming
The extent of bond-formation and bond-breaking along a
reaction pathway is provided by the concept of bond order
(BO). This theoretical tool has been used to study the
molecular mechanism of chemical reactions.8 To follow the
nature of these processes, the Wiberg bond indices9 have
been computed using the natural bond orbital analysis10 as is
implemented in Gaussian 98.11 The BO values for the N–C
breaking bond at the TSs associated with the ring-opening
process are ca. 0.5, while the BO values for the Cl–C
forming bond are 0.1. These BO values, which are in
agreement with the vibrational frequencies, indicate that
these TSs are associated with high asynchronous
processes where the N–C breaking bonds are more
advanced than the Cl–C forming-bonds. Finally, the BO
values for the O–C forming bond at the TSs associated with
the ring-closure process are 0.4, while the BO values for the
Cl–C breaking bond are ca. 0.2. Therefore, these TSs
correspond also with asynchronous processes where the
Cl–C bond-breaking is more advanced than the O–C bond-
formation.
˚
and C–N breaking bonds are 2.846 and 1.734 A at TS1-2t
Figure 4. anti and eclipsed arrangements of the C2 phenyl and C3 methyl
substituents at the antiperiplanar TSs TS2-2t and TS2-2c. The TS
corresponding with the ring-closure, TS2-BC, for the 5-membered bicyclic
aziridine is also included. DDEa, in kcal/mol, are relative to the DEa for
TS2-2t.

682
L. Testa et al. / Tetrahedron 59 (2003) 677–683
2. Conclusions
ionisation mode used in mass spectra were electron impact
(EI) at 70 eV or chemical ionisation (CI).
The reaction of N-alkylaziridines with di-tert-butyl dicar-
bonate and sodium iodide in acetone was reported in
previous works as a new synthetic procedure for the
stereoselective preparation of oxazolidin-2-ones. In the
present work we found that while trans 1,2,3-trisubstituted
aziridines give trans oxazolidin-2-ones in good yield, the cis
disposition of the substituents at C2 and C3 in monocyclic
aziridines is a limiting factor for the ring expansion. Ab
initio theoretical calculations for these reactions show that
while the ring-opening process assisted by the chloride
anion is regioselective and takes place with inversion of the
carbon atom involved on the nucleophilic attack, the
subsequent ring-closure is responsible for the retention of
the configuration at the final trans oxazolidin-2-ones. On the
other hand, the hindrance that appears between the
substituents at the C2 and C3 positions of the cis monocyclic
aziridines along the intramolecular ring-closure prevents the
formation of the corresponding cis oxazolidin-2-ones.
3.2.1. (2R,3S) and (2S,3R) 3-Methylamino-2-butanol
(5b).2 A solution of trans 2,3-dimethyloxirane (20 mmol)
in methanol (30 ml) and a solution of aqueous methylamine
(40%) (3 ml) was heated in a pressure reactor at 1008C
for 8 h. After cooling, the mixture was concentrated in
vacuo affording the 3-methylamino-2-butanol (5b)2 (97%).
Colourless oil. nmax (cm21) 3351 and 2979; dH (CDCl3)
0.69 (3H, d, J¼6.6 Hz), 0.81 (3H, d, J¼6.4 Hz), 2.11 (3H,
s), 2.20 (1H, dq, J¼6.6, 3.0 Hz), 3.54 (1H, dq, J¼6.6,
3.0 Hz) and 4.60 (2H, bs); dC (CDCl3) 13.4 (q), 17.9 (q),
33.8 (q), 59.6 (d) and 67.1 (d). HRMS [EI], found: Mþ
103.1000. C5H13NO requires M 103.0997.
3.2.2. (2R,3R) and (2S,3S) 3-Methylamino-2-butanol
(6b).2 A solution of cis 2,3-dimethyloxirane (20 mmol) in
methanol (30 ml) and a solution of aqueous methylamine
(40%) (3 ml) was heated in a pressure reactor at 1008C for
8 h. After cooling, the mixture was concentrated in vacuo
affording the methylamino alcohol (6b) (98%). Colourless
oil. nmax (cm21) 3557 and 2978; dH (CDCl3) 0.46 (3H, d,
J¼6.6 Hz), 0.64 (3H, d, J¼6.6 Hz), 1.85 (3H, s), 2.81 (1H,
m), 2.67 (1H, m) and 4.01 (2H, bs); dC (CDCl3) 13.7 (q),
19.0 (q), 31.6 (q), 60.3 (d) and 68.53 (d). HRMS [CI] MHþ
104.1070. C5H14NO requires 104.1075.
3. Experimental
3.1. Computational details
All calculations were carried out with the Gaussian 98 suite
of programs.11 An extensive characterization of the PES
was carried out at the HF/6-31Gp6 level to ensure that all
relevant stationary points were located and properly
characterized. The optimizations were carried out using
the Berny analytical gradient optimization method.12 The
stationary points were characterized by frequency calcu-
lations in order to verify that the TSs have one and only one
imaginary frequency.
3.3. Synthesis of aziridines
Method (a). To an ice-cooling and stirred solution of the
appropriate amino alcohol (2)-ephedrine (3a), (þ)-pseudo-
ephedrine (4a), (2R,3S) and (2S,3R) 3-methylamino-2-
butanol (5b) or (2R,3R) and (2S,3S) 3-methylamino-2-
butanol (6b) (9 mmol) and triphenylphosphine (12.0 mmol)
in dry ether (30 ml) under a nitrogen atmosphere, was
slowly added diisopropyl azodicarboxylate (12.0 mmol) via
syringe. The stirring was continued at 08C for 24 h. A
crystalline precipitate (triphenylphosphine oxide/diisopro-
pyl hydrazinedicarboxylate complex) was filtered off and
washed with hexane/ether 1:1 (30 ml). The filtrate was
concentrate in vacuo and the crude products 1a–1d which
were used for the following reaction without further
purification.
Since the mechanism involves ionic species, the inclusion of
solvent effects is necessary in order to obtain accurate
energies. The solvent effects, acetone, was considered by
HF/6-31Gp single point calculations at stationary points
involved on the reaction using a relatively simple self-
consistent reaction field (SCRF)13 based on the polarizable
continuum model (PCM)14 of the Tomasi’s group. The
solvent used in the experimental work is acetone. Therefore,
we have used its dielectric constant at 298.0 K, 1¼20.7.
Method (b). To an ice-cooled and stirred solution of the
appropriate amino alcohol (2)-ephedrine (3a), (þ)-pseudo-
ephedrine (4a), (2R,3S) and (2S,3R) 3-methylamino-2-
butanol (5b) or (2R,3R) and (2S,3S) 3-methylamino-2-
butanol (6b) (9 mmol) in chloroform (36 ml) was slowly
added thionyl chloride (23.4 ml, 317 mmol) and heated at
608C for 3 h. The mixture was then cooled at 08C, treated
with water (15 ml), alkalinized with aqueous NaOH 5 M,
stirred at room temperature for 24 h and extracted with
dichloromethane (3£100 ml). The organic extracts were
dried with Na2SO4, filtered and concentrated to afford the
crude products 1a–1d which were used for the following
reaction without further purification.
3.2. General procedures
Unless otherwise specified, materials were purchased from
commercial suppliers and used without further purification.
Analytical thin layer chromatography was performed on
Merck silica gel (60 F254) plates and flash column
chromatography was accomplished on Merck Kieselgel 60
(230–240 mesh). Melting points were determined with a
Kofler hot-stage apparatus and are uncorrected. Optical
rotations were measured at room temperature in a Perkin
Elmer 241 polarimeter. IR spectra were recorded for KBr
discs using a FT-IR spectrometer. 1H and 13C NMR spectra
were recorded on Bruker AC-300 spectrometer. Chemical
shifts (d) are reported in ppm with TMS as a internal
standard. High-resolution mass spectra were obtained using
a VG Autospec, TRIO 1000 (Fisons) instrument. The
3.4. Synthesis of 1,3-oxazolidin-2-ones
Di-tert-butyl dicarbonate (9 mmol) in acetone (5 ml) was
added to a mixture of the appropriate crude aziridine 1a–1d

L. Testa et al. / Tetrahedron 59 (2003) 677–683
683
3. (a) Almena, J.; Foubelo, F.; Yus, M. J. Org. Chem. 1994, 59,
3210. (b) Pfister, J. R. Synthesis 1984, 14, 969.
(9 mmol) and sodium iodide (9 mmol) in acetone (10 ml)
and stirred at reflux temperature for 2 h. After removing the
solvent, the residue was purified by column chromatography
on silica gel eluting with hexane/ethyl acetate (1:1) to afford
2a or 2b.
4. Fodor, G.; Stefanovsky, J.; Kurtev, B. Monatsh. Chem. 1967,
68, 1027.
5. Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P.
J. Am. Chem. Soc. 1985, 107, 3902.
3.4.1. (4S,5S)-3,4-Dimethyl-5-phenyl-1,3-oxazolidin-2-
one (2a).4 White solid. From aziridine obtained by method
(a), 84%. From aziridine obtained by method (b), 72%. Mp
45–468C. [a]D20¼29.4 (c 3.46, CHCl3). nmax (cm21) 1757;
dH (CDCl3) 1.26 (d, 3H, J¼6.2 Hz), 2.75 (3H, s), 3.45 (1H,
m), 4.80 (1H, d, J¼8.1 Hz) and 7.28 (5H, m); dC (CDCl3)
17.1 (q), 28.5 (q), 61.1 (d), 82.2 (d), 125.7 (d), 128.6 (d),
128.7 (d), 137.4 (s) and 157.6 (s). HRMS [EI], found: Mþ
191.0941. C11H13NO2 requires M 191.0946.
6. Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab
initio Molecular Orbital Theory; Wiley: New York, 1986.
7. The activation barrier for the ring-closure step for the cis
5-membered bicyclic aziridine via TS2-BC (see Fig. 4) is ca.
4 kcal/mol less energetic than that for the acyclic intermediate
IN2-2c. In addition, the restricted C2–C3 bond-rotation at the
corresponding bicyclic intermediate favours the antiperiplanar
arrangement of both carboxymethyl and chloride substituents.
´
8. Domingo, L. R.; Andres, J.; Moliner, V.; Safont, V. S. J. Am.
Chem. Soc. 1997, 119, 6415.
9. Wiberg, K. B. Tetrahedron 1968, 24, 1083.
3.4.2. (4S,5S)1(4R,5R)-3,4,5-Trimethyl-1,3-oxazolan-2-
one (2b). Colourless oil. From aziridine obtained by method
(a) 80%. From aziridine obtained by method (b) 75%. nmax
(cm21) 1730; dH (CDCl3) 1.18 (3H, d, J¼6.2 Hz), 1.33 (1H,
d, J¼6.2 Hz), 2.70 (3H, s), 3.21 (1H, m) and 4.04 (1H, m);
dC (CDCl3) 17.6 (q), 19.5 (q), 28.9 (q), 60.5 (d), 77.8 (d) and
158.4 (s). HRMS [EI], found: Mþ 129.0788. C6H11NO2
requires M 129.0789.
10. (a) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys.
1985, 83, 735. (b) Reed, A. E.; Curtiss, L. A.; Weinhold, V.
Chem. Rev. 1988, 88, 899.
11. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Mont-
gomery, J. A., Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich,
S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.;
Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.;
Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski,
J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng,
C. Y.; Nanayakkara, A.; Challacombe, M. W.; Gill, P. M.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez,
C.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian
98, Revision A.6; Gaussian, Inc.: Pittsburgh, PA, 1998.
12. (a) Schlegel, H. B. J. Comput. Chem. 1982, 3, 214.
(b) Schlegel, H. B. Geometry Optimization on Potential
Energy Surface. In Modern Electronic Structure Theory;
Yarkony, D. R., Ed.; World Scientific: Singapore, 1994.
13. (a) Tapia, O. J. Math. Chem. 1992, 10, 139. (b) Tomasi, J.;
Persico, M. Chem. Rev. 1994, 94, 2027. (c) Simkin, B. Y.;
Sheikhet, I. Quantum Chemical and Statistical Theory of
Solutions—A Computational Approach; Ellis Horwood:
London, 1995.
Acknowledgements
This work was supported by research funds provided by
´
the Ministerio de Educacion y Cultura of the Spanish
Government by DGICYT (projects PB98-1429 and PB98-
1451). All calculations were performed on a Cray-Silicon
´
Graphics Origin 2000 of the Servicio de Informatica de la
Universidad de Valencia. We are most indebted to this
center for providing us with computer capabilities. P. A.
´
thanks the Ministerio de Educacion y Cultura for a FPU
grant. L. T. thanks Generalitat Valenciana for a PhD grant.
Dr M. A. thanks Universitat de Valencia for a grant.
References
´
´
1. (a) Sepulveda-Arques, J.; Armero-Alarte, T.; Acero-Alarcon,
´
A.; Zaballos-Garcıa, E.; Yruretagoyena Solesio, B.; Ezquerra-
Carrera, J. Tetrahedron 1996, 52, 2097. (b) Testa, M. L.; Hajji,
14. (a) Cances, M. T.; Mennunci, V.; Tomasi, J. J. Chem. Phys.
1997, 107, 3032. (b) Cossi, M.; Barone, V.; Cammi, R.;
Tomasi, J. Chem. Phys. Lett. 1996, 255, 327. (c) Barone, V.;
Cossi, M.; Tomasi, J. J. Comp. Chem. 1998, 19, 404.
´
´
´
C.; Zaballos-Garcıa, E.; Garcıa-Segovia, A. B.; Sepulveda-
Arques, J. Tetrahedron: Asymmetry 2001, 12, 1369.
2. Bafford, R. A.; Chanon, F.; Chanon, M.; Metzger, J. Bull.
Chem. Soc. Fr. 1973, 971.