Microwave-assisted ring expansion of N-acetyl 3′-unsubstituted aziridine in the presence of Lewis acids

Article abstract of DOI:10.1016/S0040-4020(01)00123-5

The microwave-assisted ring expansion of N-acetyl 3′-unsubstituted aziridine-2-imides and N-acetyl 3′-unsubstituted aziridine-2-esters to oxazolines is reported. The regioselectivities of the rearrangements depend upon the reaction conditions, such as the Lewis acid selected and the solvent.

Full text of DOI:10.1016/S0040-4020(01)00123-5

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2807±2812
Microwave-assisted ring expansion of N-acetyl 30-unsubstituted
aziridine in the presence of Lewis acids
Giuliana Cardillo,p Luca Gentilucci, Massimo Gianotti and Alessandra Tolomelli
Á
Dipartimento di Chimica ªG. Ciamicianº, Universita degli Studi di Bologna and C.S.F.M., via Selmi 2, 40126 Bologna, Italy
Received 2 November 2000; revised 2 January 2001; accepted 18 January 2001
AbstractÐThe microwave-assisted ring expansion of N-acetyl 30-unsubstituted aziridine-2-imides and N-acetyl 30-unsubstituted aziridine-
2-esters to oxazolines is reported. The regioselectivities of the rearrangements depend upon the reaction conditions, such as the Lewis acid
selected and the solvent. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
line-4-imides, under complete regiocontrol and with
retention of the con®gurations. These results show that the
presence of an alkyl substituent at C30 of the imide deriva-
tive strongly favors the formation of oxazoline-4-imides.
The same protocol, carried out on 30-unsubstituted aziri-
dines, afforded a mixture of regioisomers, whose ratio
strongly depended on the Lewis acid selected for the acti-
vation and on the reaction conditions. These observations
prompted us to further investigate the ring expansion of 30-
unsubstituted-aziridines.
In recent years there has been an increasing interest in
the use of aziridine-2-carboxylates1 as intermediates for
the synthesis of biologically active compounds, such as a-
and b-amino acids or b-lactam antibiotics.
In this ®eld we have developed a new strategy towards the
synthesis of stereode®ned aziridines. Indeed, we obtained
aziridine-2-carboxylate derivatives following several
synthetic pathways, such as the well known Gabriel±
Cromwell reaction performed on unsaturated chiral imides2
or the 1,4-addition of O-benzylhydroxylamine to a,b-
unsaturated imides, followed by cyclization to the corre-
sponding trans aziridine.3 The stereochemical results of
both these reactions were controlled using 1,5-dimethyl-4-
phenylimidazolidin-2-one as a chiral auxiliary. This hetero-
cycle is available in both enantiomerically pure forms,
starting from (1)- or (2)-ephedrine.4
2. Results and discussion
The aziridine 1 was synthesized following the procedure
reported elsewhere.2,3 The ring expansion of 1 to afford 2
or 3 was performed in the presence of several Lewis acids in
equimolar amounts with respect to 1, in different solvents,
under normal conditions at room temperature (Scheme 1).
The results obtained are reported in Table 1.
N-Acyl activated aziridines easily afford ring opening in the
presence of a nucleophile through an SN2 mechanism1 or
can be transformed into the corresponding oxazolines
through a ring expansion reaction in the presence of
Lewis acids.5 The ring expansion of activated aziridines
promoted by azaphilic Lewis acids has recently been the
object of attention and both chemical evidence and ab initio
calculations show that this reaction occurs with retention of
the pre-existing stereogenic centers.5,6 These results have
The selected data, reported in Table 1, show that
MgBr2´Et2O favors the formation of oxazoline 2, while
BF3´Et2O gives oxazoline 3 as the major product. This result
shows that the reaction could occur via attack of the
carbonyl at both C30 and C20 ring carbon atoms, depending
1
been con®rmed by us through H NMR experiments7a and
chemical transformations,7b performed on the optically
active trans N-acyl-3-substituted aziridine-2-imides. These
compounds spontaneously rearrange in CHCl3, in the
absence of Lewis acid, affording exclusively trans oxazo-
Keywords: aziridine; oxazoline; microwaves; Lewis acids; rearrangement.
Corresponding author. Tel.: 151-2599570; fax: 151-2099456; e-mail:
cardillo@ciam.unibo.it
p
Scheme 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00123-5

2808
G. Cardillo et al. / Tetrahedron 57 (2001) 2807±2812
Table 1. Ring expansion of aziridine 1 to oxazolines 2 and 3
Entry
Lewis acid (1 equiv.)
Solvent
Yield 213 (%) 2:3 (%)a
1
3
5
6
BF3´Et2O
Cu(OTf)2
MgBr2´Et2O
MgBr2´Et2O
THF
THF
70
60b
30:70
40:60
70:30
99:1
Toluene 70c
THF
50d
a
Determined on the basis of 1H NMR analysis of the crude reaction
mixture.
b
Traces of products deriving from aziridine ring opening and starting
material were detected in the crude reaction mixture.
A 30% amount of starting material was recovered.
Conversion .95%. A 50% amount of ring opening products was detected
in the reaction mixture.
c
Scheme 2.
d
3 not being detected in the crude reaction mixture. A lower
yield and diastereoselectivity was obtained in toluene (entry
5). When the ring expansion of aziridine 1 was performed in
the presence of an equimolar amount of BF3´Et2O, we
observed the preferential formation of oxazoline 3 both in
toluene (entry 2) and in THF (entry 1).
on the Lewis acid. Anyway, although all reactions go to
complete conversion of the starting aziridine, a careful
product analysis showed the presence of regioisomeric
oxazolines and ring opening products, deriving from
hydrolysis to esters or amides, or halo compounds, deriving
from nucleophilic attack by metal halides.8
When the aziridine 1 was subjected to microwave irra-
diation in the presence of 1 equiv. of CeCl3´6H2O,
compound 4 was exclusively obtained in quantitative
yield. Furthermore, when oxazoline 2 was treated under
the same conditions, 4 was quantitatively recovered
(Scheme 2). These results show that both ring expansion
and ring opening by means of water as nucleophile can
occur on aziridine 1.
In order to avoid complex product mixtures, we performed
this reaction following a microwave-assisted methodology.9
In fact, it is reported that some reactions proceed faster
when submitted to microwave irradiation in comparison
with conventional heating and the presence of byproducts
is strongly reduced.10
The ring expansion was then performed promoting the reac-
tion with microwave irradiation at 240 W for 10 min. Under
these conditions, the reaction temperatures were 55±608C.
Comparative experiments have been carried out in different
solvents and in the presence of Lewis acids. The results
obtained are reported in Table 2.
Compound 4 was even obtained when we tried to purify
oxazoline 2 by ¯ash chromatography on silica gel. The
structure of 4 was determined through the H NMR signal
multiplicity and con®rms the regiochemistry attributed to
oxazoline 2.
1
The non-destructive removal of the chiral auxiliary under
Evans' conditions,12 by means of LiOOH in THF/H2O,
followed by treatment with CH2N2, furnished (R)-N-acetyl-
serine methyl ester 6 (Scheme 3). The regio- and stereo-
chemistry of both the acid 5 and the ester 6 were
con®rmed by comparison with the data reported in the
literature.13
The regioisomeric oxazolines have been separated by ¯ash
chromatography performed on alumina, eluting with cyclo-
hexane/ethyl acetate 7:3. Compound 3 is quite unstable and
was not isolated in pure form.11
The results obtained con®rm the trend observed in the reac-
tions performed at room temperature. In fact, complete
regioselectivity was observed when the reaction was
promoted by MgBr2´Et2O in THF (entry 6), the oxazoline
Finally, the (2S)-N-acetylaziridine methyl ester 7, prepared
as reported in the literature starting from N-trityl-(S)-
serine,14 was submitted to ring expansion under microwave-
assisted conditions (Scheme 4).
Table 2. Microwave-assisted ring expansion of aziridine 1 to oxazolines 2
and 3
Entry
Lewis acid (1 equiv.)
Solvent
Yield 213 (%) 2:3 (%)a
1
2
3
4
5
6
7
BF3´Et2O
BF3´Et2O
THF
Toluene
Toluene .95
.95
85
15:85
30:70
30:70
56:44
65:45
99:1
Cu(OTf)2
Zn(OTf)2
THF
.95
70
.95
50c
MgBr2´Et2Ob
MgBr2´Et2O
AlMe2Clc
Toluene
THF
THF
25:75
a
Determined on the basis of 1H NMR analysis of the crude reaction
mixture.
Although the reaction mixture appeared very clean, the yield and regio-
selectivity were not always reproducible, for the low solubility of the
Lewis acid.
b
c
Conversion .95%. Several products deriving from aziridine ring opening
were detected in the crude reaction mixture.
Scheme 3.

G. Cardillo et al. / Tetrahedron 57 (2001) 2807±2812
2809
in energy with respect to the MgBr2±1 complex, and shows
the presence of a six-membered ring with a highly
delocalized positive charge, for the formation of a new
imidazolidin-2-one carbonyl oxygen±C3 bond.
To simulate the following ring closure to oxazoline, we
shortened the N-acetyl carbonyl oxygen±C3 distance and
increased the imidazolidin-2-one carbonyl oxygen±C3
distance in intermediate 9. Minimization of this structure
gave the stable oxazoline-4-imide MgBr2 complex 10,
which is 16.9 kcal/mol more stable than the MgBr2±1
complex.
Scheme 4.
The reaction was carried out in toluene and in the presence
of several Lewis acids such as MgBr2´Et2O, BF3´Et2O,
Cu(OTf)2 and Zn(OTf)2. After 45 min the crude mixtures
showed oxazoline 8 as the major product, the presence of
traces of the starting aziridine and byproducts deriving from
oxazoline ring opening. The structure of oxazoline 8 was
con®rmed on the basis of H NMR15 and MS analysis.
These ®ndings allow us to deduce the existence of a
neighboring group participation effect exerted by the
imidazolidin-2-one carbonyl oxygen, which gives a strong
contribution to the stability of the incoming positive charge
on C3 during the aziridine ring opening, leading to the
formation of a stable carbocationic intermediate. The
stabilizing effect is also present in the following ring closure
to oxazoline, on the whole determining an acceleration of
the ring expansion of aziridine-2-imide with respect to the
ring expansion of aziridine-2-ester, in agreement with our
observations.
1
These results show that the aziridine-2-imide 1 rearranges to
oxazoline faster than the aziridine-2-ester 7, suggesting the
possibility that the oxazolidin-2-one substituent could exert
a neighboring group participation effect.16
To rationalize the regiochemistry reversal observed in the
ring expansion of 1 in the presence of different Lewis acids,
and in particular in the presence of BF3 and MgBr2, we
investigated the properties of the MgBr2±1 and the BF3±1
complexes, and the reaction intermediates, by means of
semi-empirical calculations.17
On the contrary, ring opening at C2 gave rise to the very
unstable intermediate complex 11, which is 19.8 kcal/mol
higher in energy than MgBr2±1, and shows the presence of a
®ve-membered ring, for the interaction of imidazolidin-2-
one carbonyl with C2. The following cyclization gave
oxazoline-5-imide complex 12. This compound results
rather high in energy, 12.8 kcal/mol with respect to
MgBr2±1, probably due to an unfavorable chelation
geometry.
The MgBr2±1 complex was evaluated by means of semi-
empirical PM3 calculations, and its more stable structure
among a set of 100 conformations generated by a Monte-
carlo procedure18 is reported in Fig. 1. In this MgBr2±1
structure,19 the Lewis acid coordinates both the carbonyl
oxygen and the aziridine nitrogen and for this reason the
aziridine ring is turned towards the exocyclic carbonyl. We
also considered MgBr2 coordination at different positions,
but each calculated complex resulted higher in energy.
According to the mechanistic model proposed, the high
regioselectivity observed experimentally for aziridine ring
opening in the presence of MgBr2 can be attributed to the
marked difference both in the energies of intermediates 9
and 11, and in the energies of the oxazoline complexes 10
and 12.
It is generally accepted that the N-acetyl aziridine ring
opening in the presence of a Lewis acid coordinated to
aziridinic nitrogen occurs via a ®rst C±N break, leading to
a carbocationic-like transition state,5a or to a carbocationic
intermediate,6 followed by the ring closure to oxazoline.
According to this mechanism, we increased the C3±N
distances to simulate the ring opening at the C3 position,
and to ®nd out a possible role of oxazolin-2-one carbonyl.
Next we studied the effect of BF3 on the regiochemistry of
the ring expansion of 1. To perform semiempirical AM1
calculations, BF3 was replaced by BH3, and the preferred
conformation of the BH3±1 complex was evaluated by
minimization of a 200 conformation set generated by a
Montecarlo procedure. The lower minimum obtained
The minimization of this high energy structure gave the
intermediate 9.20 This structure is only 2.4 kcal/mol higher
Figure 1.

2810
G. Cardillo et al. / Tetrahedron 57 (2001) 2807±2812
15:85 ratio. On the other hand, aziridine-2-ester 7 gave after
45 min only oxazoline-4-ester 8. On the basis of semi-
empirical calculations, the different reaction rates observed
for the ring expansion of the aziridine-2-imide and the
aziridine-2-ester can be attributed to the existence of a
neighboring group participation effect exercised by the
imidazolidin-2-one chiral auxiliary. In the same way, the
regioselectivity reversal observed in the ring expansion of
1 to oxazoline 2 or 3 in the presence of MgBr2 or BF3 can be
attributed to the different geometries assumed by the two
Lewis acid±1 complexes, which allow the imidazolidin-2-
one to exert its neighboring group participation effect in the
C3 or in the C2 aziridine position, respectively.
Figure 2.
4. Experimental
4.1. General
resulted in the structure shown in Fig. 221 which, with
respect to the the MgBr2±1 complex, shows the aziridine
ring and the exocyclic carbonyl turned away from each
other. Also in this case alternative complexes were calcu-
lated. Actually, the alternative coordination of BH3 to the
acetyl oxygen gave a slightly more stable compound, but
this situation does not allow the proper aziridine activation,
which is necessary for the ring expansion.5,6 Indeed, it has
been suggested that BF3 should preferably complex the
acetyl oxygen rather than the aziridinic nitrogen, but the
two complexes are in equilibrium.5,6
Unless stated otherwise, chemicals were obtained from
commercial sources and used without further puri®cation.
CH2Cl2 was distilled from P2O5. Toluene was distilled from
molecular sieves. Flash chromatography was performed on
Merck silica gel 60 (230±400 mesh) or Alumina PF254 (Typ
E). NMR Spectra were recorded with a Gemini Varian
spectrometer at 300 or 200 MHz (1H NMR) and at
75 MHz (13C NMR). Chemical shifts are reported as d
values relative to the solvent peak of CDCl3 set at dˆ7.27
(1H NMR) or dˆ77.0 (13C NMR). Infrared spectra were
recorded with an FT-IR Nicolet 205 spectrometer. Aziridine
1 was prepared following a previously reported method-
To simulate the ring opening at the C2 position, we
increased the C2±N distance. The minimization of this
high energy structure gave the intermediate 13.22 This struc-
ture is 17 kcal/mol higher in energy with respect to the
BH3±1 complex, and shows the formation of a ®ve-
membered ring with a highly delocalized positive charge.
To simulate the following ring closure to oxazoline, we
shortened the N-acetyl carbonyl oxygen±C2 distance and
increased the imidazolidin-2-one carbonyl oxygen±C2
distance in intermediate 13. Minimization of this structure
gave the stable oxazoline-5-imide BH3 complex 14, which
is 24.9 kcal/mol more stable than the BH3±1 complex.
ology.2,3 (2S)-N-Acetylaziridine methyl ester
7 was
prepared as reported in the literature starting from the trityl
derivative.11 Focused microwave irradiations were carried
out with a SynthwaveTM 402 Prolabo microwave reactor
(monomode system, 300 W) which has a variable spin rota-
tion, visual control, irradiation monitored by PC, infrared
measurement and continuous feedback of the temperature
control.
4.1.1. (4R,5S,30R)-1,5-Dimethyl-3-[(10-acetyl-20-aziridinyl)-
carbonyl]-4-phenylimidazolidin-2-one (1). White waxy
In the alterative ring opening at the C3 position to give
oxazoline-4-imide, the neighboring group participation of
the imidazolidin-2-one carbonyl oxygen seems more
dif®cult. Indeed, no stable intermediate leading to oxazo-
line-4-imide could be calculated after breaking the C3±N
bond, starting from the preferred conformation of BH3±1
reported in Fig. 2. This mechanism gives a rationale for the
experimental observation that the ring opening of aziridine
1 in the presence of BF3 affords preferentially oxazoline-5-
imide 3.
solid; IR (nujol) 1728, 1703, 1699 cm21
;
1H NMR
(CDCl3) d 0.80 (d, 3H, Jˆ6.9 Hz), 1.88 (s, 3H), 2.48 (m,
2H), 2.83 (s, 3H), 3.93 (dq, 1H, Jˆ6.9, 8.7 Hz), 4.74 (dd,
1H, Jˆ3.0, 5.4 Hz), 5.27 (d, 1H, Jˆ8.7 Hz), 7.1±7.4 (m,
5H); 13C NMR (CDCl3) d 14.9, 23.9, 28.2, 31.3, 34.5,
54.2, 59.5, 126.8, 128.2, 128.5, 135.7, 155.2, 166.8, 181.0;
20
[a]D ˆ2144 (c 1.2 in CHCl3); C16H19N3O3 (301.34): calcd
C 63.77, H 6.36, N 13.94; found C 63.74, H 6.37, N 13.92.
4.2. General procedure for the ring expansion of
aziridine 1 to oxazolines 2 and 3
3. Conclusion
To a stirred solution of aziridine 1 (30 mg, 0.1 mmol) in
toluene (3 mL) the Lewis acid (1 equiv., 0.1 mmol) was
added and the mixture was submitted to microwave irradia-
tion (Power 80%, 240 W) for 10 min. The solution was then
diluted with EtOAc (5 mL), washed with water, dried over
Na2SO4 and the solvent removed under reduced pressure.
Compounds 2 and 3 were separated by ¯ash chroma-
tography on alumina (cyclohexane/EtOAc 7:3 as eluent)
and obtained as yellow oils with the yield reported in
In this paper we describe the microwave-assisted ring
expansion of 3-unsubstituted aziridine-2-imide 1 and aziri-
dine-2-ester 7 to oxazoline in the presence of several Lewis
acids. This reaction occurs with different reaction rates and
regioselectivities. In particular, in the presence of MgBr2,
aziridine-2-imide 1 gave after 10 min the oxazoline-4-imide
2 as the only regioisomer, while in the presence of BF3 it
gave after 10 min a mixture of 2 and oxazoline-5-imide 3 in

G. Cardillo et al. / Tetrahedron 57 (2001) 2807±2812
2811
1
Table 2. Compound 3 is quite unstable and was not isolated
in pure form.11
5. Mp 119±121; H NMR (D2O) d 1.98 (s, 3H), 3.75 (dd,
1H, Jˆ12.0, 6.6 Hz), 3.81 (dd, 1H, Jˆ12.0, 3.7 Hz), 4.30
(dd, Jˆ6.6, 3.7 Hz); 13C NMR (D2O) d 25.3, 60.2, 65.4,
20
4.2.1.
(4R,40R,50S)-4,5-Dihydro-2-methyl-4-[(10,50-di-
177.1, 179.0; [a]D ˆ213.9 (c 1.2 in EtOH); MS m/z 147
methyl-40-phenylimidazolidin-20-on-30yl)carbonyl]oxazole
(M1, 22), 105 (100), 60 (42); C5H9NO4 (147.13): calcd C
1
(2). IR (®lm) 1728, 1702, 1686 cm21; H NMR (CDCl3) d
40.82, H 6.17, N 9.52; found C 40.77, H 6.16, N 9.52.
0.82 (d, 3H, Jˆ6.6 Hz), 2.05 (s, 3H), 2.85 (s, 3H), 3.94 (dq,
1H, Jˆ6.6, 8.7 Hz), 4.42 (m, 1H), 4.46 (dd, 1H, Jˆ8.9,
12.3 Hz), 5.33 (d, 1H, Jˆ8.7 Hz), 5.89 (t, 1H, Jˆ8.9 Hz),
7.1±7.4 (m, 5H); 13C NMR (CDCl3) d 14.0, 15.2, 28.3, 54.2,
59.3, 68.3, 69.7, 127.0, 128.1, 128.4, 135.8, 153.9, 165.8,
1
6. H NMR (CDCl3) d 2.09 (s, 3H), 3.81 (s, 3H), 3.94 (dd,
1H, Jˆ11.2, 3.6 Hz), 4.02 (dd, 1H, Jˆ11.2, 4.0 Hz), 4.70
(ddd, Jˆ3.6, 4.0 Hz, 7.4 Hz), 6.54 (d, 1H, Jˆ7.4 Hz); 13C
NMR (CDCl3) d 23.2, 50.9, 54.8, 63.6, 171.8, 173.6;
C6H11NO4 (161.16): calcd C 44.72, H 6.88, N 8.69; found
C 44.75, H 6.89, N 8.72.
20
170.0; [a]D ˆ261.8 (c 0.3 in CHCl3); C16H19N3O3
(301.34): calcd C 63.77, H 6.36, N 13.94; found C 63.78,
H 6.32, N 13.95.
4.3. General procedure for the ring expansion of
aziridine 7 to oxazoline 8
4.2.2. (5R,40R,50S)-4,5-Dihydro-2-methyl-5-[(1,5-dimethyl-
4-phenylimidazolidin-20-on-30yl)carbonyl]oxazole (3). IR
(®lm) 1732, 1704, 1666 cm21; 1H NMR (CDCl3) d 0.82 (d,
3H, Jˆ6.6 Hz), 1.99 (s, 3H), 2.84 (s, 3H), 3.87 (dd, 1H, Jˆ
6.2, 13.5 Hz), 3.97 (dq, 1H, Jˆ6.6, 8.8 Hz), 4.29 (dd, 1H,
Jˆ13.5, 10.8 Hz), 5.26 (d, 1H, Jˆ8.8 Hz), 5.96 (dd, 1H, Jˆ
6.2, 10.8 Hz), 7.05±7.4 (m, 5H). 13C NMR (CDCl3) d 13.7,
15.0, 28.2, 29.7, 54.6, 59.3, 59.9, 126.8, 128.3, 128.6, 135.8,
151.8, 159.7, 169.6.
To a stirred solution of aziridine 7 (30 mg, 0.2 mmol) in
toluene (3 mL) the Lewis acid (1 equiv., 0.2 mmol) was
added and the mixture was submitted to microwave irradia-
tion (Power 80%, 240 W) for 45 min. The solution was then
diluted with EtOAc (5 mL), washed with water, dried over
Na2SO4 and the solvent removed under reduced pressure.
Compound 8 was obtained as a yellow oil by ¯ash chroma-
tography on silica gel (cyclohexane/EtOAc 3:7 as eluent).
The yield depends upon the Lewis acid selected (40±75%).
4.2.3.
(4R,5S,30R)-1,5-Dimethyl-3-(20-acetamido-30-
hydroxypropionyl)-4-phenylimidazolidin-2-one (4). To
a stirred solution of aziridine 1 (30 mg, 0.1 mmol) or oxazo-
line 2 (30 mg, 0.1 mmol) in toluene (3 mL), CeCl3´6H2O
(1 equiv., 36 mg) was added and the mixture was submitted
to microwave irradiation (Power 80%, 240 W) for 10 min.
The solution was then diluted with EtOAc (5 mL), washed
with water, dried over Na2SO4 and the solvent removed
under reduced pressure. Compound 4 was puri®ed by ¯ash
chromatography on silica gel (cyclohexane/EtOAc 8:2 as
eluent) and isolated as colorless oil in 96% yield (31 mg).
IR (®lm) 3353, 1730, 1702, 1662 cm21; 1H NMR (CDCl3) d
0.81 (d, 3H, Jˆ6.6 Hz), 1.93 (s, 3H), 2.84 (s, 3H), 3.95 (m,
2H), 4.05 (dq, 1H, Jˆ6.6, 8.1 Hz), 5.27 (d, 1H, Jˆ8.1 Hz),
6.03 (dt, 1H, Jˆ7.5, 4.5 Hz), 6.58 (d, 1H, Jˆ7.5 Hz), 7.1±
7.4 (m, 5H); 13C NMR (CDCl3) d 14.9, 23.2, 28.2, 54.1,
54.5, 59.9, 64.5, 126.7, 128.2, 128.6, 135.8, 155.0, 170.2,
4.3.1. (4S)-2-Methyl-4-methoxycarbonyloxazoline (8). IR
(®lm) 1732, 1704, 1666 cm21; 1H NMR (CDCl3) d 2.07 (s,
3H), 3.79 (s, 3H). 4.35 (dd, 1H, Jˆ3.8, 11.8 Hz), 4.48 (dd,
1H, Jˆ4, 11.8 Hz), 4.87 (dd, 1H, Jˆ3.8, 4 Hz); 13C NMR
(CDCl3) d 13.7, 53.2, 68.6, 69.4, 166.9, 171.3; MS m/z 143
(M1, 29), 133 (20), 111 (30), 105 (26), 101 (69), 91 (73), 85
(74), 83 (100), 79 (42); C6H9NO3 (143.14): calcd C 50.35, H
6.34, N 9.79; found C 50.37, H 6.33, N 9.82.
Acknowledgements
We thank M. U. R. S. T. (60% and Co®n '98) and Bologna
University (Funds for Selected Topics) for ®nancial support
of this research.
172.9; [a]D ˆ245.0 (c 0.4 in CHCl3); MS m/z 319 (M1,
20
5), 262 (100), 183 (77), 108 (55), 51 (26); C16H21N3O4
(319.36): calcd C 60.17, H 6.63, N 13.16; found C 60.14,
H 6.59, N 13.09.
References
4.2.4. (2R)-N-Acetylserine (5), (2R)-N-acetylserine methyl
ester (6). Hydrogen peroxide (0.4 mmol, 40 ml 30% p/v
soln.) and LiOH (5 mg, 0.22 mmol) were added at 08C to
a solution of 4 (31 mg, 0.1 mmol) in THF (4 mL) and water
(1 mL). After 2 h, the reaction was quenched with sat.
Na2SO3 and the mixture extracted with EtOAc. The organic
layer was dried over Na2SO4 and the solvent was removed
under reduced pressure to give (4R,5S)-1,5-dimethyl-4-
phenylimidazolidin-2-one (17 mg, 90%). The aqueous
layer was acidi®ed to pH 2, extracted twice with EtOAc
and the solvent removed under reduced pressure. (2R)-N-
Acetylserine 5 was obtained in 85% yield (15 mg) as a white
solid. The residue was diluted with Et2O (2 mL) and treated
with an excess of CH2N2 in Et2O for 2 h. The solvent was
then removed under reduced pressure to afford methyl ester
6 in 95% yield (16 mg) as a waxy solid.
1. (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599±
619. (b) McCoull, W.; Davis, F. A. Synthesis 2000, 1347±
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Asymmetry 1997, 8, 1693±1715.
2. Cardillo, G.; Gentilucci, L.; Tomasini, C.; Visa Castejon-
Bordas, M. P. Tetrahedron: Asymmetry 1996, 7, 755±762.
3. (a) Cardillo, G.; Casolari, S.; Gentilucci, L.; Tomasini, C.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1848±1849.
(b) Bongini, A.; Cardillo, G.; Gentilucci, L.; Tomasini, C.
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898±899.
5. (a) Hori, K.; Nishiguchi, T.; Nabeja, A. J. Org. Chem. 1997,
62, 3081±3088. (b) Gant, T. G.; Meyers, A. I. Tetrahedron
1994, 50, 2297±2360.

2812
G. Cardillo et al. / Tetrahedron 57 (2001) 2807±2812
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14. Nakajima, K.; Takai, F.; Tanaka, T.; Okawa, K. Bull. Chem.
Soc. Jpn 1978, 51, 1577±1578.
1998, 63, 4568±4569 (and references cited therein).
7. (a) Cardillo, G.; Gentilucci, L.; Tolomelli, A.; Tomasini, C.
Tetrahedron Lett. 1997, 38, 6953±6956. (b) Cardillo, G.;
Gentilucci, L.; Tolomelli, A. Tetrahedron Lett. 1999, 40,
8261±8264.
15. Bucciarelli, M.; Forni, A.; Moretti, I.; Prati, F.; Torre, G.
Tetrahedron: Asymmetry 1995, 6, 2073±2080.
16. Armaroli, S.; Cardillo, G.; Gentilucci, L.; Gianotti, M.;
Tolomelli, A. Org. Lett. 2000, 2, 1105±1107.
17. Performed by means of hyperchem 5.1 Release Pro for
Windows Molecular Modeling System (Hypercube Inc.,
Copyright q 1999).
18. Performed by means of chemplustme Release (Hypercube
Inc., Copyright q 1993±1997).
8. Righi, G.; D'Achille, R.; Bonini, C. Tetrahedron Lett. 1996,
37, 6893±6896.
9. Cardillo, G.; Gentilucci, L.; Gianotti, M.; Tolomelli, A.
Synlett 2000, 9, 1309±1311.
10. (a) Caddick, S. Tetrahedron 1995, 51, 10403±10432.
(b) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.;
Ê
19. For MgBr2±1 interatomic distances: C3±Nˆ1.50 A, C2±Nˆ
Ê
Ê
Á
Jacquault, P.; Mathe, D. Synthesis 1998, 1213±1233.
1.51 A, imidazolidin-2-one carbonyl oxygen±C2ˆ2.73 A,
Ê
imidazolidin-2-one carbonyl oxygen±C3ˆ3.85 A.
(c) Stambouli, A.; Chastrette, M.; Sou®aoui, M. Tetrahedron
Lett. 1991, 32, 1723±1724.
Ê
20. For 9 interatomic distances: C3±Nˆ2.50 A, imidazolidin-2-
Ê
one carbonyl oxygen±C3ˆ1.54 A, N-acetyl carbonyl
11. Cardillo, G.; Gentilucci, L.; Tolomelli, A.; Tomasini, C.
Synlett 1999, 11, 1727±1730 (In this paper the more stable
(5R,40R,50S)-4,5-dihydro-2-phenyl-5-[(10,50-dimethyl-40-phenyl-
imidazolidin-20-on-30yl)carbonyl]oxazole was isolated and
fully characterized).
Ê
oxygen±C3ˆ3.31 A.
Ê
21. For BH3±1 interatomic distances: C2±N and C3±Nˆ1.48 A,
Ê
imidazolidin-2-one carbonyl oxygen±C2ˆ2.73 A, imidazo-
Ê
lidin-2-one carbonyl oxygen±C3ˆ4.07 A.
Ê
22. For 13 interatomic distances: C2±Nˆ2.53 A, imidazolidin-2-
12. Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 83±91.
13. (a) Pogliani, L.; Ziessow, D. Tetrahedron 1979, 35, 2865±
2873. (b) Maruyama, K.; Hashimoto, M.; Tamiaki, H.
J. Org. Chem. 1992, 57, 6143±6150.
Ê
one carbonyl oxygen±C2ˆ1.50 A, N-acetyl carbonyl
Ê
oxygen±C2ˆ3.08 A.