1,3-Dipolar cycloaddition of N-substituted dipolarophiles and nitrones: Highly efficient solvent-free reaction

Article abstract of DOI:10.1021/jo702490w

(Chemical Equation Presented) New isoxazolidines were synthesized in good to excellent yields by 1,3-dipolar cycloaddition of N-vinylamide dipolarophiles and nitrones. Strikingly, solvent-free conditions gave high conversion and yields, shortened reaction time, and minimized degradation products. N-Vinyloxazolidin-2-one and its analogues used in these cycloaddition reactions were conveniently prepared in excellent yields by a modified version of Buchwald's one-step copper-catalyzed vinylation using vinyl bromide. From the adducts, a two-step access to various unsymmetric aspartate derivatives was also described.

Full text of DOI:10.1021/jo702490w

1,3-Dipolar Cycloaddition of N-Substituted Dipolarophiles and
Nitrones: Highly Efficient Solvent-Free Reaction
Thanh Binh Nguyen, Arnaud Martel, Robert Dhal,* and Gilles Dujardin*
UCO2M 6011 CNRS, UniVersite´ du Maine, 72085, Le Mans, France
robert.dhal@uniV-lemans.fr; gilles.dujardin@uniV-lemans.fr
ReceiVed NoVember 22, 2007
New isoxazolidines were synthesized in good to excellent yields by 1,3-dipolar cycloaddition of
N-vinylamide dipolarophiles and nitrones. Strikingly, solvent-free conditions gave high conversion and
yields, shortened reaction time, and minimized degradation products. N-Vinyloxazolidin-2-one and its
analogues used in these cycloaddition reactions were conveniently prepared in excellent yields by a
modified version of Buchwald’s one-step copper-catalyzed vinylation using vinyl bromide. From the
adducts, a two-step access to various unsymmetric aspartate derivatives was also described.
Introduction
(Scheme 1) could concern a novel enantioselective access to
unsymmetric aspartate derivatives.
1,3-Dipolar cycloaddition reactions of nitrones with alkenes
offer one of the most powerful routes to isoxazolidines.1,2
Reductive cleavage of the nitrogen-oxygen bond of such adducts
gives 3-amino alcohols.2 Therefore, nitrone cycloaddition can
afford a versatile way for construction of nitrogen-containing
carbon skeletons. Numerous applications of isoxazolidine ad-
ducts have been reported in total synthesis, often based on their
ease to be transformed into polyfunctional amines including
γ-amino alcohols, â-amino ketones and esters.3 Inverse-electron-
demand 1,3-dipolar cycloaddition has mostly been studied with
vinyl ethers,4 vinyl esters,5 and N-acyloxazolones.6 Our work
focused on the cycloaddition between a nitrone bearing a
protecting group (PG) on nitrogen and a N-vinylcarbamate as
dipolarophile. An interesting application for these adducts
We have recently published a study on the 1,3-dipolar
cycloaddition of N-substituted dipolarophiles and nitrones.7 This
first investigation began with the reaction under several Lewis
acid catalyzed and thermal conditions (in solution). The best
results were obtained under noncatalyzed thermal conditions
(refluxing toluene). In this paper, we wish to report an optimized
procedure to achieve the cycloaddition between a nitrone and a
N-vinyl(amide/carbamate/imide) involving solvent-free condi-
tions in very short reaction time (up to less than 1 min) with
little or no formation of degradation products.
Enamides, which serve as versatile intermediates for synthe-
sizing nitrogen-containing compounds, have been prepared to
date by various methods including acylation of imines,8
condensation of amides and aldehydes,9 metal-catalyzed10 or
(1) For reviews of cycloaddition of nitrones, see: (a) Padwa, A., Ed. In
1,3-Dipolar Cycloaddition Chemistry; Wiley-Interscience: New York, 1984;
Vols. 1-2. (b) DeShong, P.; Lander, S. W., Jr.; Leginus, J. M.; Dicken, C.
M. In AdVances in Cycloaddition; Curran, D. P., Ed.; JAI Press: Greenwich,
CT, 1988; Vol. 1, pp 87-128. (c) Carruthers, W. Cycloaddition Reaction
in Organic Synthesis; Pergamon Press: Oxford, 1990. (d) Little, R. D. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol 5, pp 239-270. (e) Gotheft, K. V.; Jørgensen,
K. A. Chem. ReV. 1998, 98, 863.
(4) (a) Tamura, O.; Mita, N.; Imai, Y.; Nishimura, T.; Kiyotani, T.;
Yamasaki, M.; Shiro, M.; Morita, N.; Okamoto, I.; Takeya, T.; Ishibashi,
H.; Sakamoto, M. Tetrahedron 2006, 62, 12227. (b) Ashizawa, T.; Ohtsuki,
N.; Miura, T.; Ohya, M.; Shinozaki, T.; Ikeno, T.; Yamada, T. Heterocycles
2006, 68, 1801.
(5) Chiacchio, U.; Corsaro, A.; Gumina, G.; Romeo, R. J. Org. Chem.
1999, 64, 9322.
(6) Ishizuka, T.; Matsunaga, H.; Iwashita, J.; Arai, T.; Kunieda, T.
Heterocycles 1994, 37, 715.
(7) Nguyen, T. B.; Gaulon, C.; Chapin, T.; Tardy, S.; Tatiboue¨t, A.;
Rollin, P.; Dhal, R.; Martel, A.; Dujardin, G. Synlett 2006, 19, 3255.
(8) (a) Brossi, A.; Dolan, L. A.; Teitel, S. Org. Synth. 1977, 56, 3. (b)
Boeckmann, R. K., Jr.; Goldstein, S. W.; Walter, M. A. J. Am. Chem. Soc.
1988, 110, 8250.
(2) (a) Torsell, K. B. G. Nitrile Oxides, Nitrones and Nitronates in
Organic Syntheses; VCH: New York, 1988; Vol. 20. (b) Frederickson, M.
Tetrahedron 1997, 53, 403.
(3) Padwa, A.; Pearson, W. H. Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Towards Heterocycles and Natural Products; John
Wiley and Sons: Hoboken, NJ, 2003.
10.1021/jo702490w CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/11/2008
J. Org. Chem. 2008, 73, 2621-2632
2621

Nguyen et al.
TABLE 1. Preparation of N-Vinylamides
SCHEME 1
entry amide
X
R1
H
R2
H
N-vinylamide yield (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
O
O
O
O
3a
3b
3c
3d
3e
3f
92
100
95
95
92
Me Me
H
Et
H
Ph
H
H
NMe
phthalimide
20
strong base-induced11 isomerization of N-allylamides, elimina-
tion of alcohols from N-(alkoxyalkyl)amides,12 addition of
amides to acetylenes,13 metal-catalyzed coupling of alkenes and
amides,14 and trans vinylation using alkyl vinyl ethers15 or vinyl
carboxylates,16 vinyl bromides/iodides and amides.17 As an
extension of the Buchwald’s method,17a we report a one-step
procedure for synthesizing vinylamides from unsubstituted vinyl
bromide/iodide and amides.
TABLE 2. Preparation of N-Alkenyloxazolidin-2-ones
alkenyl
entry bromide
yield
alkenylamide (%)
Results and Discussion
R
R′
1
2
3
4
5
2b
2c
2d
2e
2f
Me
Me
Ph
H
H
Me
H
3g
3h
3i
3j
3k
95
95
98
98
95
Preparation of Aza-Substituted Dipolarophiles. Alkeny-
lamides are conveniently prepared by the Buchwald’s one-step
procedure based on the copper-catalyzed direct vinylation of
amide nitrogen using vinyl bromides.17 To the best of our
knowledge, such vinylation has never been employed to
unsubstituted vinyl bromide and from a more general point of
view, there has been no one-step practical method for synthesiz-
ing vinylamides from unsubstituted vinyl bromide/iodide and
amides.
4-MeO-C6H4
H
4-NO2-C6H4
of vinyl bromide (2 equiv) which was charged at 0 °C, this
procedure afforded N-vinylamides in excellent yields (92-
100%) (Table 1, entries 1-5). The coupling is not affected by
the nature of substituent at C-4 of oxazolidinone (Table 1, entries
2-4). Vinylation could also be carried out with phthalimide
(Table 1, entry 6) despite the low yield (20%).
Considering the high volatility of vinyl bromide (bp 6 °C) in
regard to high temperature required for coupling reaction, we
carried out the reaction in a sealed tube. Using a slight excess
Alkenylamides were also prepared by this method (Table 2).
Two volatile homologues of vinyl bromide, (Z)-propenyl
bromide (2b), and 2-methylpropenyl bromide (2c) were utilized
in excess (1.5 equiv) in order to consume all oxazolidin2-one
after the reaction. Applying this procedure to â-styryl bromides
(2d-f) gave also excellent yields. In these cases, the benzene
ring can bear an electron donating group (Table 2, entry 4) or
an electron withdrawing group (entry 5). The configuration of
the double bond was retained. In all cases, a simple filtration
through Celite of the crude reaction mixture followed by solvent
elimination is sufficient to furnish pure products which could
be used in the next step.
Cycloaddition Conditions Optimization. The reaction be-
tween N-benzyl-R-carbonyloxyalkylnitrone (e.g., 4a) and â-un-
substituted vinyl amides provided good yields in refluxing
toluene. However, when another nitrone was employed (namely
N-benzyl-R-arylnitrone 4b-d), varying yields of isoxazolidine
adducts were observed, possibly because of the long reaction
time which resulted in partial degradation. In order to extend
the scope of the cycloaddition to various nitrones, we needed
to find more efficient conditions that could accelerate the
reaction rate and minimize the degradation. In the literature,
many authors reported the cycloaddition of N-benzyl-R-carbo-
nyloxyalkylnitrone with alkenes or vinyl ethers/esters.4 Under
these conditions, dipolarophiles were utilized as solvent or in
large excess with or without catalyst. However, vinyl amides
can hardly be used as solvent or in large excess because of their
(9) (a) Smith, M. B.; Wang, C. J.; Keusenkothen, P. F.; Dembofsky, B.
T.; Fay, J. G.; Zezza, C. A.; Kwon, T. W.; Sheu, J.; Son, Y. C.; Menezes,
R. F. Chem. Lett. 1992, 247. (b) Zezza, C. A.; Smith, M. B. Synth. Commun.
1987, 17, 729.
(10) (a) Stille, J. K.; Becker, Y. J. Org. Chem. 1980, 45, 2139. (b)
Neugnot, B.; Cintrat, J. C.; Rousseau, B. Tetrahedron 2004, 60, 3575. (c)
Zhang, S. W.; Mitsudo, T.; Kondo, T.; Watanabe, Y. J. Organomet. Chem.
1995, 485, 55. (d) Otsuka, S.; Tani, K. Synthesis 1991, 9, 665. (e) Corriu,
R.; Huynh, V.; Roreau, J.; Pataud-Sat, M. J. Organomet. Chem. 1983, 255,
358. (f) Yamada, H.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1981, 56,
4569. (g) Tatsumi, T.; Hashimoto, K.; Tominaga, H.; Mizuta, K.; Hata, K.;
Hidai, H.;Uchida, Y. J. Organomet. Chem. 1983, 252, 105. (h) Onishi, M.;
Oishi. S.; Sakaguchi, M.; Takaki, I.; Kiraki, K. Bull. Chem. Soc. Jpn. 1986,
56, 3925. (i) Akita, M.; Yasuda, M.; Nagasuka, K.; Nakamura, K. Bull.
Chem. Soc. Jpn. 1983, 56, 554.
(11) (a) Riberrau, P.; Delamare, M.; Celanire, S.; Queguiner, G.
Tetrahedron Lett. 2001, 42, 3571. (b) Beak, P.; Lee, B. J. Org. Chem. 1989,
54, 458. (c) Tischler, A. N.; Tischler, M. H. Tetrahedron Lett. 1978, 37,
3407-3410. (d) Bortolussi, M.; Bloch, R.; Conia, J. M. Tetrahedron Lett.
1977, 26, 2289.
(12) (a) Torii, S.; Inokuchi, T.; Kubota, M. J. Org. Chem. 1985, 50,
4157. (b) Shono, T.; Matsumura, U.; Tsubata, K.; Sugihara, Y.; Yamane,
S. I.; Kanazawa, T.; Aoki, T. J. Am. Chem. Soc. 1982, 104, 6697. (c) Gaulon,
C.; Gizecki, P.; Dhal, R.; Dujardin, G. Synlett 2002, 6, 952.
(13) (a) Ziegenbein, W.; Franke, W. Chem. Ber. 1957, 90, 2271. (b)
Reppe, W. et al. Liebigs Ann. Chem. 1956, 601, 134.
(14) Hosokawa, T.; Takano, M.; Kuroki, Y.; Murahashi, S. I. Tetrahedron
Lett. 1992, 33, 6643.
(15) (a) Walles, W. E.; Toussignant, W. F.; Houtman, Y. J. U.S. Pat.
1959, US 2891058, (b) Bakke, W. W. U.S. Pat. 1962, US 3033829.
(16) Murray, R. E. U.S. Pat. 1992, US 5155253.
(17) (a) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett.
2003, 5, 3667. (b) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809.
2622 J. Org. Chem., Vol. 73, No. 7, 2008

1,3-Dipolar Cycloaddition of Dipolarophiles and Nitrones
TABLE 3. 1,3-Dipolar Cycloaddition of 3/4: Comparison between Solution- and Solvent-Free Conditions
cycloaddition in
solvent-free
refluxing solutiona
cycloadditionb
trans/cis
ratiod
entry enamide
R1
R2
R3
nitrone R4
R5
adduct
solvent
time yieldc (%)
time
T (°C) yieldc (%)
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3b
3b
3g
3h
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4a
4d
4a
4a
Bn CO2Et
Bn Ph
Bn 4-F-Ph
Bn 4-CF3Ph
Ph Ph
Bn CO2Et
Bn 4-CF3Ph
Bn CO2Et
Bn CO2Et
5a
5b
5c
5d
5e
5f
toluene
24 h
91
53
20
0
10 min
3 d
10 h
2 h
30 min
10 min
2 h
10 h
3 d
110
110
140
160
110
110
160
110
110
99
96
80
82
89
95
75
70
4:1
1:2.3
1.15:1
1:4
p-xylene 13 d
p-xylene 6 d
p-xylene 3 d
toluene
toluene
p-xylene 6 d
toluene
toluene
H
6 d
24 h
80
89
20
50
1:8
Me
Me
H
10:1
3.3:1
8:1e
5g
5h
3 d
3 d
H
Me Me
0f
0f
a 1 mmol of enamide and 1 mmol of nitrone were heated in 5 mL of solvent. b 1 mmol of enamide and 1 mmol of nitrone were heated at indicated
1
temperature. c Isolated yields of separated diastereoisomers or mixture of two diastereoisomers. d Based on H NMR of crude mixture. e The two isomers
with a trans C4-C5 relationship were not observed. f No reaction, enamide was recovered.
commercial unavailability and the difficult removal. In order
to extend the scope of the thermal cycloaddition, solvent-free
reactions appeared to be an interesting way. Under these
conditions at 110 °C, the cycloaddition between stoichiometric
amount of nitrone 4a and N-vinyloxazolidin-2-one 3a proved
to be complete after 30 min without any formation of side-
products and any effect on the stereoselectivity. At this
temperature, melted nitrone 4a and enamide 3a form a
homogeneous mixture that ensures close contact. Both reaction
conditions (refluxing toluene/xylene vs solvent-free) were
summarized in Table 3. The reactions leading to good yields
of expected cycloadducts in refluxing toluene were performed
with a dramatic decrease in reaction time (∼200 times) under
solvent-free conditions (Table 3, entries 1, 5, and 6). The
sluggish reaction of N-benzyl-R-arylnitrone 4b-d in toluene was
also accelerated with less degradation in solvent-free system
and thus simplifying the purification process (Table 3, entries
2-4, and 7).
FIGURE 1. 2D NOESY correlation for adducts 5.
When 3g bearing a Z-â-methyl group was used as dipolaro-
phile, the cycloaddition with nitrone 4a took place much more
slowly than its unsubstituted homologues and did not go to
completion in refluxing toluene. Under solvent-free conditions,
Figure 1 for compound cis-5a, trans-5a, cis-5e, and trans-5h.
Three NOESY correlation peaks (between H-3 and H-4â,
between H-4â and H-5, between H-5 and H-3) confirm the cis-
the reaction was achieved after 10 h at 110 °C with partial
relationship between the two substituents at C-3 and C-5 in cis-
degradation of nitrone 4a (Table 3, entry 8) and with an
5a and cis-5e. Besides the presence of two NOESY correlation
interesting stereoselectivity. In case of â,â-dimethyl dipolaro-
peaks (between H-5 and H-4â, between H-4R and H-3 in trans-
phile 3h, no trace of adduct was observed after 3 days of heating
5a; between H-3 and CH3 at C-4, between H-4 and H-5 in trans-
5h), the absence of NOESY correlation peak between H-3 and
H-5 helped to deduce the trans relationship between oxazoli-
dinone and carbonyloxyethyl moieties in trans-5a and trans-
(Table 3, entry 9) under both conditions.
From unsubstituted N-vinyloxazolidin-2-one 3a, N-benzyl-
isoxazolidines 5a-d were obtained with various trans or cis
stereoselectivities, dependent on the nature of the nitrone
5h. The Z geometry of dipolarophile 3g was retained in the
substituent: trans-ester isoxazolidine 5a is mainly obtained from
major adduct 5h (total absence of NOESY correlation peak
between H-5 and CH3 at C-4) in full agreement with the
concerted nature of the thermal cycloaddition.
4a, whereas aryl isoxazolidines 5b-d are obtained in most cases
with a cis selectivity (Table 3, entries 1-4). In contrast, a trans
selectivity is observed for both adducts 5f,g deriving from the
4,4-disubstituted N-vinyloxazolidin-2-one 3b (Table 3, entries
6 and 7). Moreover, it should be noticed that the N-phenyl
adduct 5e was efficiently obtained with a good cis selectivity
(Table 3, entry 5).
All cycloadditions between 4a and 2-styryloxazolidin-2-ones
(3i-l, Scheme 2) failed to occur, regardless of double bond
configuration of the enamides (Z in 3i and 3j; E in 3k and 3l)
or the electronic nature of the benzene ring p-substituent
(electron withdrawing group, e.g., 3j, or electron-donating group,
e.g., 3k) (Scheme 2). Obviously, this cycloaddition depends
The relative configuration of all adducts could be unambigu-
ously elucidated from NOESY experiments as exemplified in
J. Org. Chem, Vol. 73, No. 7, 2008 2623

Nguyen et al.
TABLE 4. Solvent-Free Cycloaddition of 4a with Chiral N-Vinyloxazolidin-2-ones 3c,da
R1
R2
product
% yieldb
diastereomeric ratioc trans-1/trans-II/cis-1/cis-II d
trans/cis ratioc
H
Et
Ph
H
5i
5j
93
93
49 (3S,5S):20 (3R,5R):20 (3S,5R):11 (3R,5S)e
42 (3R,5R):28 (3S,5S):17 (3S,5R)e:13 (3R,5S)
69:31
70:30
a 3c,d (1.05 equiv). b Global yield of purified product after SiO2 chromatography. c The ratio was determined from 1H NMR analysis of the crude product.
d Absolute configurations of all diastereomers were obtained after correlation with (S)-aspartic acid (vide infra). e This cis isomer was separated from the
three others by SiO2 chromatography.
SCHEME 2. Unsuccessful Cycloaddition of 3i-l and 4a
strongly on the steric hindrance at the double bond â-position
in the dipolarophile.
FIGURE 2. Isomerism of 4a and use of cyclic 4f.
Asymmetric Extension Using Chiral Dipolarophiles. The
dipolar cycloaddition was next studied starting from chiral
N-vinyloxazolidin-2-ones 3c,d and nitrone 4a (Table 4). Under
the thermal solvent-free conditions, the reaction was achieved
within 10 min at 110 °C, leading to cycloadducts in high yields
after purification. However, in both cases, the adducts 5i and
5j were obtained as a mixture of diastereomers resulting from
low trans/cis (≈ 7:3) and facial (e4:1) selectivities. As for
adducts 5a-e, the cis/trans ratio was established on the base
and as E/Z equilibrating mixtures in solvent at room temperature
(Figure 2).19
Consequently, cycloaddition of nitrone 4a often leads to
mixtures of cis/trans diastereomers.1e Lewis acids can be used
to chelate the Z geometry of the double bond and to accelerate
the cycloaddition reaction rate.20 However, in our case, neither
satisfactory yield nor good selectivity has ever been obtained
with Lewis acid conditions (Eu(fod)3, Cu(OTf)2, ZnBr2) due to
degradation of the starting materials.
A convenient way to circumvent this problem consists in
using nitrones with fixed geometry. We considered that the
lactonic nitrone 4f (Figure 2) could be the ideal dipole for this
purpose since it could both ensure a good cis/trans selectivity
due to its stable 6-membered ring configuration and could also
act as a good chiral inducer due to the proximity of its
stereogenic center. This chiral nitrone was designed, prepared
in enantiopure form and successfully used in dipolar cycload-
dition toward alkenes and alkenyl ethers by Tamura et al.21
Using solvent-free conditions for the cycloaddition between
nitrone 4f and dipolarophiles 3a, 3b, 3m, and 3f, we obtained
the adducts in very short reaction time (the fastest reaction was
completed after less than 1 min) and very good diastereoselec-
tivities (Table 5).
1
of the H NMR signal peaks of H-5 proton, which display a
higher chemical shift for both cis isomers than for trans ones.
The moderate trans selectivity so observed appears as lower
than those obtained with achiral dipolarophiles 3a and 3b.
Before attempting to improve the facial control, we first tried
to define new conditions that would ensure an efficient trans/
cis control.
Asymmetric Extension with Chiral (E)-Geometry-Fixed
R-Alkoxycarbonylnitrones. If we assume a concerted mech-
anism, the thermal 1,3-dipolar cycloaddition between a nitrone
and an alkene is a [π4s + π2s]-type process similar to the Diels-
Alder reaction.18 The lower cis/trans stereoselectivity in nitrone
cycloaddition compared to the Diels-Alder reaction can be
explained by the Z / E isomerization of nitrone moiety during
the cycloaddition. Nitrones bearing an electron-withdrawing
group such as 4a are known to exist in Z form in solid phase
The bicyclic core of cycloadducts 6-9 increases the rigidity
of the system and their common (2R,3aR,7R) configuration, for
(19) (a) Aurich, H. G.; Franzke, M.; Kesselheim, H. P. Tetrahedron 1992,
48, 663. (b) Jensen, K. B.; Hazell, R. G.; Jorgensen, K. A. J. Org. Chem.
1999, 64, 2353.
(18) Carruthers, W. Some Modern Methods of Organic Synthesis;
Cambridge University Press: Cambridge, U.K., 1986; pp 256-262.
2624 J. Org. Chem., Vol. 73, No. 7, 2008

1,3-Dipolar Cycloaddition of Dipolarophiles and Nitrones
TABLE 5. Solvent-Free Cycloaddition of 4f with 3a
FIGURE 3. 2D NOESY correlation for adducts 7 and 9.
the unique or the major diastereomer, could therefore be readily
assigned on the basis of spectral data, including 2D COSY and
NOESY NMR spectra, as exemplified in Figure 3 for compound
7 and 9. Four NOESY correlation peaks (between H-1 and H-4b,
H-4b and H-5, H-5 and H-1, and between H-3 and H-4a)
confirm this structure.
Conversion of Adducts 5a and 5f into N-Aspartyloxazo-
lidin-2-ones 10a,b. New 5-azaisoxazolidines such as 5 could
be transformed into useful derivatives via N-O bond cleavage.
The reductive ring opening of 5-carbaisoxazolidines into 1,3-
aminoalcohols is well documented, using reducing agents such
as Zn/H+,22 H2/Pd,23 SmI224.... However, such methods have
not been successfully applied to 5-oxaisoxazolidines or 5-azai-
soxazolidines up to date. In our case, starting from adducts 5,
these procedures led to the recovery of starting materials or to
the formation of complex mixtures.
N-Quaternarization mediated ring opening of isoxazolidine
has been also described as an effective method to cleave the
N-O bond.25 The procedures using alkylating agents (BnBr,
MeI, Me2SO4...) in solution with or without subsequent basic
treatment (DABCO, Et3N, NaH...) were applied to 5-carba- or
a Enamides (1 equiv). b Purified product was obtained as a mixture of
two isomers. c Purified product was obtained as a single isomer. d The ratio
was determined from H NMR analysis of crude mixture.
1
SCHEME 3. Ring Opening of Isoxazolidine via
N-Quaternarization Using Benzyl Bromide
(20) (a) Kanemasa, S.; Uemura, T.; Wada, E. Tetrahedron Lett. 1992,
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Kanemasa, S.; Tsuruoka, T.; Yamamoto, H. Tetrahedron Lett. 1995, 36,
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Miyawaki, T.; Sakamoto, M. J. Chem. Soc., Chem. Commun. 1996, 1861.
(l) Katagiri, N.; Okada, M.; Kaneko, C.; Furuya, T. Tetrahedron Lett. 1996,
37, 1801. (m) Castellari, C.; Lombardo, M.; Pietropaolo, G.; Trombini, C.
Tetrahedron: Asymmetry 1996, 7, 1059. (n) Tokunaga, Y.; Ihara, M.;
Fukumoto, K. Tetrahedron Lett. 1996, 37, 6157. (o) Naito, T.; Shirikawa,
M.; Ikai, M.; Ninomiya, I.; Kiguchi, T. Recl. TraV. Chim. Pays-Bas 1996,
115, 13. (p) Tamura, O.; Mita, N.; Gotanda, K.; Yamada, K.-I.; Nakano,
T.; Sakamoto, M. Heterocycles 1997, 46, 95. (q) Degiorgis, F.; Lombardo,
M.; Trombini, C. Tetrahedron 1997, 53, 11721. (r) Degiorgis, F.; Lombardo,
M.; Trombini, C. Synthesis 1997, 1243. (s) Kashima, C.; Takahashi, K.;
Fukuchi, I.; Fukusaka, K. Heterocycles 1997, 44, 289. (t) Minakata, S.;
Ezoe, T.; Nakamura, K.; Ryu, I.; Komatsu, M. Tetrahedron Lett. 1998, 39,
5205.
(21) Tamura, O.; Gotanda, K.; Terashima, R.; Kikuchi, M.; Miyawaki,
T.; Sakamoto, M. Chem. Commun. 1996, 1861.
(22) Karatholuvhu, M. S.; Sinclair, A.; Newton, A. F.; Alcaraz, M. L.;
Stockman, R. A.; Fuchs, P. L. J. Am. Chem. Soc. 2006, 128, 12656.
(23) Liautard, V.; Christina, A. E.; Desvergnes, V.; Martin, O. R. J. Org.
Chem. 2006, 71, 7337.
(24) Caubert, V.; Langlois, N. Tetrahedron Lett. 2006, 47, 4473.
(25) (a) DeShong, Ph.; Dicken, C. M.; Staib, R. R.; Freyer, A. J.;
Weinreb, St. M. J. Org. Chem. 1982, 47, 4397. (b) Murahashi, S-I.; Kodera,
Y.; Hosomi, T. Tetrahedron Lett. 1988, 29, 5949. (c) Casuscelli, F.;
Chiacchio, U.; Rescifina, A.; Romeo, G.; Romeo, R.; Tomassini, S.; Uccella,
N. Tetrahedron 1995, 51, 2979. (d) Meske, M. J. Prakt. Chem. 1997, 339,
426. (e) Bayon, P.; de March, P.; Figueredo, M.; Font, J. Tetrahedron 1998,
54, 15691. (f) Defoin, A.; Chevrier, C. Synthesis 2003, 8, 1221.
5-azaisoxazolidines to afford â-amino ketones or â-amino acid
esters respectively in high yields. To the best of our knowledge,
such methods have never been reported to furnish â-amino acid
amides from 5-aza-isoxazolidines. Therefore, we tested 5a and
5f as model substrates to generate new â-amino acid imides
10a and 10b (Scheme 3). By applying these literature proce-
dures, we observed low conversions and the formation of
elimination side products, especially when a base (Et3N) was
used.25c The presence of these products (fumarate derivatives,
trialkylamine) rendered the purification difficult. The required
optimization of this reaction was conducted with benzyl bromide
chosen by its ability to act as N-protecting reagent. Interestingly,
we found that using 3 equiv of BnBr without solvent at 50 °C
for 3 days led to the clean and total conversion of 5a and 5f
J. Org. Chem, Vol. 73, No. 7, 2008 2625

Nguyen et al.
TABLE 6. Access to Unsymmetric Aspartate Derivatives 11-16
from N-Acyloxazolidin-2-ones 10a,b
SCHEME 4. Formation of Imide 17
SCHEME 5. Asymmetric Access to Aspartate Estersa
R
conditions
Nu
yield (%)
H
Me
H
LiOH , THF/H2O (1:1), rt, 30 min
LiOH , THF/H2O (1:1), rt, 30 min
BnOLi, THF, rt, 30 min
NaOMe, MeOH, rt, 30 min,
then Amberlyst 15
OH
OH
OBn
OMe
80
85
76
90
H
H
MeONH2MeCl, AlMe3, CH2Cl2,
0 °C, 30 min
NMeOMe
83
H
H
n-BuNH2 (10 equiv),10 min
NH2GlyOMe‚HCl, AlMe3, CH2Cl2,
0 °C, 2 h
NH-n-Bu
NHGlyOMe
90
79
into 10a and 10b, respectively (Scheme 3). The formation of
the N,N-dibenzylisoxazolidinium intermediate was not observed,
suggesting a spontaneous and fast ring-pening step. After basic
treatment of the crude ammonium salt, imides 10a and 10b were
obtained in excellent yields.
Access to Unsymmetric Aspartate Derivatives from N-As-
partyloxazolidin-2-ones 10a,b. Having in hand these new
imides 10a,b (in racemic form), we investigated the access to
(() unsymmetric aspartate derivatives by chemoselective attack
of an heteronucleophile on the amide carbonyl. Many nonde-
structive removals of oxazolidin-2-one moieties have been
reported, based on the transformation of N-acyloxazolidin-2-
one into acid,26 ester,27 Weinreb amide,28 amide,29 and alde-
hyde.30
a Reactions and conditions: (i) BnBr, neat, 50 °C, 3 d; (ii) EtONa, EtOH,
rt; (iii) (a) EtOH, AcCl, (b) BnBr, K2CO3(aq), ∆.
access to aspartate derivatives exemplified the specific synthetic
utility of 5-azaisoxazolidines 5 with regard to their 5-oxa
analogues.
When ethanolamine was used as nucleophile in THF, suc-
cinimide 17 was obtained in high yield as a result of a double
attack of the nucleophilic amine function to the amide and the
ethyl ester carbonyl groups (Scheme 4).
Adapting these conditions to the highly functionalized deriva-
tives 10a and 10b, we obtained a wide range of products in
high yields, including acid 11, benzyl and methyl ester 12 and
13, Weinreb’s amide 14, N-butylamide 15, and glycine dipeptide
16 (Table 6). In all cases, the oxazolidin-2-one moiety proved
to be a good leaving group, and all the tested nucleophiles
attacked exclusively at the amide carbonyl. This chemoselective
Asymmetric Access to Unsymmetric Aspartate Deriva-
tives. The N-quaternarization-mediated ring-opening reaction
of isoxazolidines 5i,j deriving from chiral N-vinyloxazolidin-
2-ones 3c,d was investigated on the mixture of the three
unseparable diastereomers (diastereomeric ratios: (3S,5S)/
(3R,5R)/(3S,5R) ) 58:21:21 for 5i and (3R,5R)/(3S,5S)/(3R,5S)
) 48:43:9 for 5j). Previously optimized conditions (BnBr in
excess without solvent at 50 °C for 3 days) led to the clean and
total conversion into 10c and 10d/ respectively, each as a pair
of diastereomers in 75:25 and 56:44 ratios, respectively (Scheme
5). To our delight, we found that both diastereomers of 10c
and of 10d were easily separable by conventional SiO2
chromatography and isolated in pure form, leading respectively
to (3S)-10c and (3R)-10c in 69% and 21% yields and to (3R)-
10d and (3S)-10d in 53% and 42% yields. The absolute
configuration of the major diastereomers (3S)-10c and (3R)-
10d was established after ethanolysis and comparison between
the specific rotations of the diethyl aspartates 18 so obtained
(-112.4 and +113.7, respectively) and of the diethyl ester of
N,N-dibenzyl-L-aspartic acid (-110.3). In order to fulfill the
stereochemical assignment for 5i and 5j, the same transformation
was applied to the pure isomers (3R,5S)-5i and (3S,5R)-5j,
(26) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127. (b) Kleschick, W. A. J. Org. Chem. 1986, 51, 5429.
(27) (a) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc.
1984, 106, 4261. (b) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am.
Chem. Soc. 1982, 104, 1737. (c) Evans, D. A.; Bartroli, J.; Shih, T. L. J.
Am. Chem. Soc. 1981, 103, 2127.
(28) (a) Braddock, D. C.; Brown, J. M. Tetrahedron: Asymmetry 2000,
11, 3591. (b) Xu, Z.; Chen, Z.; Ye, T. Tetrahedron: Asymmetry 2004, 15,
355.
(29) (a) Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew. Chem.,
Int. Ed. 2002, 41, 4569. (b) Evans, D. A.; Barnes, D. M.; Johnson, J. S.;
Lectka, T.; von Matt, P.; Miller, S. J.; Murry, J. A.; Norcross, R. D.;
Shaughnessy, E. A.; Campos, K. R. J. Am. Chem. Soc. 1999, 121, 7582.
(c) Tsutomu, Y.; Akio, A.; Shiroshi, S. J. Org. Chem. 1994, 59, 3506. (d)
Miyata, O.; Shinada, T.; Ninomiya, I,. Naito, T.; Tetrahedron Lett. 1991,
32, 3519. (e) Burlingame, M. A.; Mendoza, E.; Ashley, G. W. Tetrahedron
Lett. 2004, 45, 2961.
(30) (a) Nakata, T.; Nagao, S.; Oishi, T. Tetrahedron Lett. 1985, 26,
6465. (b) Mills, S.; Desmond, R.; Reamer, R. A.; Volante, R. P.; Shinkai,
I. Tetrahedron Lett. 1988, 29, 281. (c) White, J. M.; Tunoori, A. R.; Georg,
G. I. J. Am. Chem. Soc. 2000, 122, 11995.
2626 J. Org. Chem., Vol. 73, No. 7, 2008

1,3-Dipolar Cycloaddition of Dipolarophiles and Nitrones
General Procedure for Preparation of Alkenylamides. A
mixture of amide (10 mmol), alkenyl bromide (15 mmol for (Z)-
1-bromopropene and 2-methyl-1-bromopropene; 10 mmol for styryl
bromides), N,N′-dimethylethylenediamine (1 mmol), K2CO3 (11
mmol), CuI (0.5 mmol), and toluene (3 mL) was placed in a tightly
closed sealed tube fitted with a magnetic stirbar. The mixture was
stirred for 16 h at 113 °C and then cooled to room temperature.
The tube was carefully opened, and its contents were filtered
through celite, the solid residue was rinsed with CH2Cl2, and the
combined filtrates were evaporated to yield the vinylamides 3g-
k. These products were used in cycloaddition without further
purification.
leading to the expected imides (3R)-10c and (3S)-10d, respec-
tively, in pure form.
This easy conversion into both enantiomers of diethyl
aspartate 18 strongly suggests that the efficient access to both
diastereomers of 10c and 10d in pure forms described here could
offer a practical entry to unsymmetrical aspartates 11-16 of
both L and D series, via simple treament of the L or D imide
precursor with the appropriate heteronucleophile.
Conclusion
We have found convenient conditions to achieve the 1,3-
dipolar cycloaddition between nitrones and enamides: a thermal
solvent-free reaction which allowed the reaction to complete
in short time, avoided the degradation and gave excellent yields
of adducts in comparison with reaction in solvent. This thermal
solvent-free cycloaddition is strongly influenced by steric
hindrance of the substituent at the â-position of the enamide
double bond. When the geometry-fixed nitrone 4f was used as
dipole, a high facial selectivity was observed. Representative
monocyclic adducts were thus transformed in two steps and high
yields into unsymmetric aspartate derivatives. An asymmetric
extension of this pathway was pointed out with chiral dipo-
larophiles via diastereomeric separation of the imide intermedi-
ates. This transformation is not efficient with adducts derived
from the cycloaddition of alkyl vinyl ethers as dipolarophiles.
We have also extended successfully the Buchwald’s vinylation
to obtain enamides which are important synthetic intermediates.
Further applications of solvent-free cycloaddition conditions as
well as of the adducts are currently under investigation.
(Z)-3-Propenyloxazolidin-2-one (3g: 1.21 g (95%); colorless
liquid; IR (KBr) ν ) 2923, 1751, 1670, 1483, 1421, 1249, 1074
1
cm-1; H NMR (400 MHz, CDCl3) δ 6.24-6.22 (m, 1H), 5.01-
4.93 (m, 1H), 4.40 (m, 2H), 3.99 (m, 2H), 1.77-1.75 (m, 3H); 13
C
NMR (100 MHz, CDCl3) δ 156.1, 123.5, 110.4, 62.3, 45.6, 12.0;
HRMS (GC/CI+ CH4) calcd for C6H10NO2 [M + H+] 128.0712,
found 128.0696.
3-(2-Methylprop-1-enyl)oxazolidin-2-one (3h): 1.34 g (95%);
colorless oil. The characterization data match those reported in the
literature.17
(Z)-3-(2-Styryl)oxazolidin-2-one (3i): 1.85 g (98%); colorless
liquid; IR (KBr) ν ) 3078, 3054, 3024, 2991, 2915, 1759, 1653,
1415, 1239, 1070, 1036 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.34-
7.20 (m, 5H), 6.66 (d, J ) 9.9 Hz, 1H), 5.99 (d, J ) 9.9 Hz, 1H),
4.26 (t, J ) 8.0 Hz, 2H), 3.37 (t, J ) 8.0 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 157.1, 135.3, 129.1, 127.8, 126.9, 124.0, 112.6,
62.5, 44.8; HRMS (GC/CI+ CH4) calcd for C11H12NO2 [M + H+]
190.0868, found 190.0852.
(E)-3-[2-(4-Methoxyphenyl)vinyl]oxazolidin-2-one (3j): 2.14
g (98%); colorless crystals; mp 154-156 °C (dichloromethane);
1H NMR (400 MHz, CDCl3) δ 7.27 (d, J ) 8.6 Hz, 2H), 7.27 (d,
J ) 14.7 Hz, 1H), 6.85 (d, J ) 8.6 Hz, 2H), 5.74 (d, J ) 14.7 Hz,
1H), 4.50 (∼t, J ) 8.1 Hz, 2H), 3.84 (t, J ) 8.1 Hz, 2H), 3.80 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 158.7, 155.6, 128.6, 126.8,
122.5, 114.3, 110.9, 62.4, 55.4, 42.7; HRMS (DCI+ CH4) calcd
for C12H14NO3 [M + H+]; HRMS 220.0974, found 220.0990.
(Z)-3-[2-(4-Nitrophenyl)vinyl]oxazolidin-2-one (3k): 222 mg
(95%); yellow crystals; mp 163 °C (dichloromethane); IR (KBr) ν
) 2987, 2915, 1744, 1509, 1341 cm-1; 1H NMR (400 MHz, CDCl3)
δ 8.21 (m, 2H), 7.38 (m, 2H), 6.83 (d, J ) 9.9 Hz, 1H), 5.99 (d,
J ) 9.9 Hz, 1H), 4.35 (t, J ) 8.0 Hz, 2H), 3.39 (t, J ) 8.0 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 156.9, 146.5, 142.7, 130.0,
126.8, 123.2, 110.0, 62.8, 45.1; HRMS (DCI+ CH4) calcd for
C11H11N2O4 [M + H+]; HRMS 235.0719, found 235.078.
General Procedure for Preparation of N-Benzylnitrones. A
mixture of N-benzylhydroxylamine hydrochloride (1.595 g, 10
mmol), NaHCO3 (1.26 g, 15 mmol), 3 Å molecular sieves (2.00
g), and the corresponding aldehyde (10 mmol) in CH3OH (10 mL)
was stirred at room temperature for 3 h. The reaction mixture was
filtered through Celite. The filtrate was concentrated under reduced
pressure to afford the crude nitrone. The compound was further
purified by recrystallization (dichloromethane, petroleum ether).
(Z)-N-(4-Fluorobenzylidene)(phenyl)methanamine Oxide (4c).
From 4-fluorobenzaldehyde, nitrone 4c was obtained as colorless
crystals (2.12 g, 80%): mp 110-111 °C (dichloromethane);
IR (KBr) ν ) 3071, 3037, 1598, 1576, 1503, 1458, 1230, 1157,
Experimental Section
General Procedure for the Preparation of Vinylamides 3a-
f. To a tube containing the amide precursor (10 mmol), N,N′-
dimethylethylenediamine (1 mmol), K2CO3 (5.5 mmol), CuI (0.5
mmol), and toluene (3 mL) at 0 °C was injected liquid vinyl
bromide (20 mmol, cooled to 0 °C). The tube was sealed and heated
in an oil bath at 113 °C with magnetic stirring. After heating for
16 h, the tube was cooled to room temperature, carefully opened
and purged with inert gas. The mixture was filtered through Celite,
and the solid residue was rinsed with dichloromethane. The filtrate
was evaporated to yield corresponding vinylamide. The product
was used in cycloaddition without further purification.
3-Vinyl-2-oxazolidinone (3a): 1.04 g (92%); colorless oil. The
characterization data match those reported in the literature.12c
4,4-Dimethyl-3-vinyl-oxazolidin-2-one (3b): 1.41 g (100%);
colorless oil; IR (KBr): ν ) 2975, 1758, 1640, 1402, 1384, 1321
1
cm-1; colorless liquid; H NMR (400 MHz, CDCl3) δ 6.46 (dd, J
) 16.7, 10.1 Hz, 1H), 4.94 (dd, J ) 16.7, 1.0 Hz, 1H), 4.55 (dd,
J ) 10.1, 1.0 Hz, 1H), 4.03 (s, 2H), 1.49 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 155.1, 127.4, 96.4, 75.0, 58.4, 24.5; HRMS (GC/
CI+ CH4) calcd for C7H12NO2 [M + H+] 142.0868, found 142.0861.
(R)-4-Phenyl-3-vinyloxazolidin-2-one (3c): 1.80 g (95%); color-
less oil. The characterization data match those reported in the
literature.12c
1
1146 cm-1; H NMR (400 MHz, CDCl3) δ 8.28-8.23 (m, 2H),
(S)-4-Ethyl-3-vinyloxazolidin-2-one (3d): 1.34 g (95%); color-
less oil. The characterization data match those reported in the
literature.12c
1-Methyl-3-vinylimidazolidin-2-one (3e): 1.16 g (92%); color-
less liquid; 1H NMR (200 MHz, CDCl3) δ 7.00 (dd, J ) 15.8, 9.0
Hz, 1H), 4.16 (d, J ) 9.0 Hz, 1H), 4.05 (t, J ) 15.8 Hz, 1H),
3.54-3.38 (m, 4H), 2.85 (s, 3H).
2-Vinylisoindoline-1,3-dione (3f): 0.35 g (20%) from phthal-
imide and 0.34 g (20%) from potassium phthalimide (without K2-
CO3 added). The characterization data match those reported in the
literature.31
7.44-7.39 (m, 5H), 7.37 (s, 1H), 7.10-7.05 (m, 2H), 5.04 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 163.4 (d, J1C-F ) 253 Hz), 133.10;
133.05, 130.8, 129.3, 129.1, 129.0, 126.8 (d, J3C-F ) 4 Hz), 115.6
(d, J2C-F ) 21 Hz), 71.1; 19F NMR (376.5 MHz, CDCl3) δ -107,6
(tt, J ) 8.0, 5.7 Hz, 1F); HRMS (FD) calcd for C14H12NOF [M +
H+]; HRMS 229.0903, found 229.0900.
Nitrone 4f was prepared according to reported procedures.21
(31) Griesbeck, A. G.; Henz, A.; Hirt, J.; Ptatschek, V.; Engel, T.; Lo¨ffler,
D.; Schneider, F. W. Tetrahedron 1994, 50, 701.
J. Org. Chem, Vol. 73, No. 7, 2008 2627

Nguyen et al.
General Procedure for Cycloaddition in Solution (Procedure
A). A solution of the enamide (1 mmol) and the nitrone (1 mmol)
in toluene/xylene (5 mL) was heated and stirred under reflux. After
completion of the reaction (monitored by TLC, see Table 3), the
solvent was then removed under vacuum. The crude product was
purified by chromatography over silica gel column or by recrys-
tallization.
General Procedure for Solvent-Free Cycloaddition (Proce-
dure B). A mixture of enamide (1 mmol) and nitrone (1 mmol)
was heated with stirring at the temperature shown in Table 3. If
necessary, the reaction mixture was homogenized with CH2Cl2
which was then evaporated under vacuum prior to heating. The
crude product was purified by chromatography over silica gel
column or by recrystallization.
cis-Ethyl 2-Benzyl-5-(2-oxooxazolidin-3-yl)isoxazolidine-3-
carboxylate (cis-5a). From 3a and 4a. Purification by flash
chromatography (diethyl ether) afforded the title compound as a
pale yellow oil: Rf ) 0.4 (diethyl ether), 61 mg (19%) after
procedure A and 58 mg (18%) after procedure B; pale yellow liquid;
IR (neat) ν ) 1738, 1194, 1028 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.37-7.28 (m, 5H), 5.92 (dd, J ) 8.2, 4.1 Hz, 1H), 4.12 (m,
3H), 4.29 (m, 2H), 4.00 (dd, J ) 13.5 Hz, 1H), 3.84 (q, J ) 9.1
Hz, 1H), 3.75 (dt, J ) 9.1, 5.9 Hz, 1H), δ 3.55 (dd, J ) 9.1, 7.6
Hz, 1H), 2.87 (ddd, J ) 13.6, 9.1, 8.2 Hz, 1H), 2.57 (ddd, J )
13.6, 7.6, 4.1 Hz, 1H), 1.25 (t, J ) 7.1 Hz, 3H); 13C NMR (100
MHz (CDCl3) δ 169.8, 157.6, 135.8, 129.1, 128.2, 127.6, 81.5,
66.6, 62.3, 61.6, 61.5, 40.8, 36.3, 13.9; HRMS (DCI+ CH4) calcd
for C16H21N2O5 [M + H+]; HRMS 321.1450, found 321.1446.
trans-Ethyl 2-Benzyl-5-(2-oxooxazolidin-3-yl)isoxazolidine-3-
carboxylate (trans-5a). From 3a and 4a. Purification by flash
chromatography (diethyl ether) afforded the title compound as a
pale yellow oil: Rf ) 0.2 (diethyl ether), 230 mg (72%) after
procedure A and 260 mg (81%) after procedure B; pale yellow
liquid; IR (neat) ν ) 1737, 1182, 1034 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.38-7.27 (m, 5H), 5.84 (dd, J ) 7.9, 4.4 Hz, 1H), 4.30
(t, J ) 7.3 Hz, 2H), 4.19 (d, J) 14.4 Hz, 1H), 4.17 (d, J) 14.4
Hz, 1H), 4.11 (m, 2H), 3.74 (m, 1H), 3.54 (t, J ) 7.9 Hz, 2H),
2.83 (ddd, J ) 13.3, 7.9, 6.9 Hz, 1H), 2.55 (ddd, J ) 13.3, 7.9, 4.4
Hz, 1H), 1.28 (t, J) 7.1 Hz, 3H); 13C NMR (100 MHz (CDCl3) δ
169.1, 157.0, 135.6, 129.1, 128.1, 127.5, 81.9, 65.1, 61.9, 61.3,
60.1, 40.2, 35.1, 14.0; HRMS (DCI+ CH4) calcd for C16H21N2O5
[M + H+]; HRMS 321.1450, found 321.1455.
68.6, 62.1, 58.8, 41.5, 40.0; HRMS (DCI+ CH4) calcd for
C19H21N2O3 [M + H+]; HRMS 325.1552, found 325.1551.
cis-3-(2-Benzyl-3-(4-fluorophenyl)isoxazolidin-5-yl)oxazolidin-
2-one (cis-5c). From 3a and 4c. Purification by flash chromatog-
raphy (cyclohexane/ethyl acetate 8:2) afforded the title compound
as a colorless oil which crystallizes on standing: Rf ) 0.40 (diethyl
ether); 34 mg (10%) after procedure A and 127 mg (37%) after
procedure B; IR (KBr) ν ) 2984, 2957, 1741, 1507, 1257, cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.43-7.38 (m, 2H), 7.32-7.22 (m,
5H), 7.09-7.04 (m, 2H), 5.91 (dd, J ) 8.1, 5.0 Hz, 1H), 4.34-
4.24 (m, 2H), 3.93 (d, J ) 14.4 Hz, 1H), 3.88-3.81 (m, 2H), 3.73-
3.68 (m, 1H), 3.66 (d, J ) 14.4 Hz, 1H), 2.97 (ddd, J ) 13.6, 8.1,
7.6), 2.28 (ddd, J ) 13.6, 9.9, 5.0); 13C NMR (100 MHz, CDCl3)
δ 162.4 (d, J1
) 247.4 Hz), 158, 137.1, 133.6 (d, J4
) 2.9
C-F
C-F
C-F
Hz), 128.9 (d, J3C-F ) 8.1 Hz), 128.6, 128.2, 127.2, 115.8 (d, J2
) 21.2 Hz), 81.2, 69.9, 62.1, 59.6, 42.8, 40.4; 19F NMR (376.5
MHz, CDCl3) -113.6 (tt, J ) 8.0, 4.6 Hz, 1F); HRMS (DCI +
methane) calcd for C19H20N2O3F [M + H+]; HRMS 343.1458,
found 343.1455.
trans-3-(2-Benzyl-3-(4-fluorophenyl)isoxazolidin-5-yl)oxazo-
lidin-2-one (trans-5c). From 3a and 4c. Purification by flash
chromatography (cyclohexane/ethyl acetate 8:2) afforded the title
compound as a colorless oil which crystallizes on standing: Rf )
0.38 (diethyl ether); 36 mg (10%) after procedure A and 146 mg
(43%) after procedure B; IR (KBr) ν ) 3063, 2957, 1741, 1507
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.44-7.40 (m, 2H), 7.24-
7.32 (m, 5H), 7.10-7.05 (m, 2H), 5.99-5.90 (br, 1H), 4.37-4.33
(m, 2H), 3.78-3.74 (m, 2H), 3.71-3.61 (m, 3H), 2.65 (m, 2H);
some characteristic signals 13C NMR (100 MHz, CDCl3) δ 163.9,
161.4, 57.1, 129.2, 128.2, 127.7, 115.9 (d, J2C-F ) 22.0 Hz), 82.2,
68.0, 62.1, 58.6, 40.5; 19F NMR (376.5 MHz, CDCl3) δ -113.3
(m, 1F).
cis-3-(2-Benzyl-3-(4-(trifluoromethyl)phenyl)isoxazolidin-5-
yl)oxazolidin-2-one (cis-5d). From 3a and 4d. Purification by
flash chromatography (diethyl ether/cyclohexane 3:1) afforded
the title compound as a colorless oil: Rf ) 0.40 (diethyl ether);
65 mg (17%) after procedure B; IR (KBr) ν ) 3059, 3022, 1746,
1502, 1250 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J ) 8.1
Hz, 1H), 7.56 (d, J ) 8.1 Hz, 1H), 7.32-7.22 (m, 5H), 5.94 (dd,
J ) 8.1, 5.1 Hz, 1H), 4.34-4.24 (m, 2H), 3.94 (d, J ) 14.1 Hz,
1H), 3.88-3.81 (m, 1H), 3.72 (d, J ) 14.1 Hz, 1H), 3.71-3.65
(m, 1H), 3.02 (ddd, J ) 13.6, 8.1, 7.3), 2.29 (ddd, J ) 13.6, 9.5,
5.1); 13C NMR (100 MHz, CDCl3) δ 157.7, 142.4, 136.7, 130.7,
128.8, 128.3, 127.6, 127.5, 126.0 (q, J4
) 3.7 Hz), 123.8
cis-3-(2-Benzyl-3-phenylisoxazolidin-5-yl)oxazolidin-2-one (cis-
5b). From 3a and 4b. Purification by flash chromatography
(cyclohexane/ethyl acetate 9:1 to 1:1) afforded the title compound
as a colorless solid: Rf ) 0.57 (diethyl ether), 119 mg (37%) after
procedure A and 217 mg (67%) after procedure B; mp 152-153
C-F
(q, J1
) 272.2 Hz), 81.4, 69.9, 62.2, 60.0, 42.8, 40.5; 19F
C-F
NMR (376.5 MHz, CDCl3) -62.6 (s, 3F); HRMS (DCI + methane)
calcd for C20H19N2O3F3 [M + H+]; HRMS 392.1348, found
392.1346.
1
°C; IR (neat) ν ) 1741, 1417, 1242, 1072, 1017 cm-1. H NMR
trans-3-(2-Benzyl-3-(4-(trifluoromethyl)phenyl)isoxazolidin-
5-yl)oxazolidin-2-one (trans-5d). From 3a and 4d. Purification by
flash chromatography (diethyl ether/cyclohexane 3:1) afforded the
title compound as a colorless oil: Rf ) 0.20 (diethyl ether); 255
mg (65%) after procedure B; IR (KBr) ν ) 3057, 3021, 1745, 1500,
(400 MHz, CDCl3) δ 7.43 (m, 2H). 7.38 (m, J ) 7 Hz, 2H), 7.32
(m, 1H), 7.29 (m, 4H), 7.26 (m, 1H), 5.92 (dd, 1H, J ) 8.4, 5.0
Hz, 1H), 4.32 (ddd, J ) 9.1, 8.4, 5.3 Hz, 1H), 4.28 (q, J) 8.4 Hz,
1H), 3.97 (d, J ) 13.6 Hz, 1H), 3.65 (d, J ) 13.6 Hz, 1H), 3.88
(q, J ) 8.4 Hz, 1H), 3.84 (dd, J ) 9.9, 7.8 Hz, 1H), 3.74 (td, J)
8.4, 5.7 Hz, 1H), 2.99 (ddd, J ) 13.6, 8.2, 7.8 Hz, 1H), 2.32 (ddd,
J ) 13.7, 9.9, 5.0 Hz, 1H); 13C NMR (100 MHz (CDCl3) δ 157.8,
138.0, 137.4, 129.0, 128.7, 128.3, 128.2, 127.4, 127.3, 81.3, 70.7,
62.2, 59.7, 43.0, 40.6; HRMS (DCI+ CH4) calcd for C19H21N2O3
[M + H+]; HRMS 325.1552, found 325.1567.
1
1251 cm-1; H NMR (400 MHz, CDCl3) δ 7.63 (d, J ) 8.1 Hz,
1H), 7.54 (d, J ) 8.1 Hz, 1H), 7.34-7.23 (m, 5H), 5.89 (dd, J )
8.1, 4.0 Hz, 1H), 4.40-4.31 (m, 2H), 3.98 (d, J ) 14.1 Hz, 1H),
4.00-3.97 (m, 1H), 3.76 (d, J ) 14.1 Hz, 1H), 3.69-3.59 (m,
2H), 2.67 (ddd, J ) 13.6, 7.6, 4.0 Hz, 1H), 2.58 (ddd, J ) 13.6,
8.8, 8.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 157, 142.4, 136.1,
129.0, 128.24, 128.18, 127.5, 125.8 (q, J3
C-F
(376.5 MHz, CDCl3) δ -62.6 (s, 3F).
) 3.7 Hz), 124.0 (q,
trans-3-(2-Benzyl-3-phenylisoxazolidin-5-yl)oxazolidin-2-
one (trans-5b). From 3a and 4b. Purification by flash chromatog-
raphy (cyclohexane/ethyl acetate 9:1 to 1:1) afforded the title
compound as a colorless solid: Rf ) 0.3 (diethyl ether); 52 mg
(16%) after procedure A and 94 mg (29%) after procedure B; mp
155 °C; IR (neat) ν ) 1741, 1416, 1244, 1076, 1014 cm-1;1H NMR
(400 MHz, CDCl3) δ 7.42-7.21 (m, 10H), 5.91 (m, 1H), 4.33-
4.29 (m, 2H), 4.01-3.81 (m, 2H), 3.70 (d, J ) 14.4 Hz, 1H), 3.56-
3.65 (m, 2H), 2.68-2.49 (m, 2H); 13C NMR (100 MHz (CDCl3) δ
157.2, 137.9, 136.6, 129.0, 128.9, 128.3, 128.2, 127.9, 127.3, 81.5,
C-F
J1
) 272.2 Hz), 81.8, 68.0, 62.1, 59.2, 41.4, 40.3; 19F NMR
cis-3-(2,3-Diphenylisoxazolidin-5-yl)oxazolidin-2-one (cis-5e).
From 3a and 4c. The crude products were purified by recrystalli-
zation (chloroform, n-hexane), 248 mg (80%) after procedure A
and 276 (89%) after procedure B. An analytically pure sample of
cis adduct was obtained in the first crop of recrystallization:
colorless crystals; mp 159-161 °C; IR (neat) ν ) 1743, 1410, 1234,
1
1018 cm-1; H NMR (400 MHz, CDCl3) δ 7.51 (d, J) 7.5 Hz,
2628 J. Org. Chem., Vol. 73, No. 7, 2008

1,3-Dipolar Cycloaddition of Dipolarophiles and Nitrones
2H). 7.39 (t, J) 7.5 Hz, 2H), 7.31 (t, J) 7.5 Hz, 1H), 7.24 (t, J)
7.5 Hz, 2H), 7.03 (d, J) 7.5 Hz, 2H), 7.00 (t, J) 7.5 Hz, 1H),
6.13 (dd, J ) 8.3, 5.3 Hz, 1H), 4.72 (dd, J ) 8.3, 6.3 Hz, 1H),
4.34 (ddd, J ) 9.1, 8.3, 5.3 Hz, 1H), 4.26 (td, J) 9.1, 8.3 Hz, 1H),
3.68 (q, J ) 8.3 Hz, 1H), 3.37 (td, 8.3, 5.3 Hz, 1H), 3.04 (ddd, 1H,
J ) 13.4, 8.4, 8.3 Hz, 1H), 2.40 (ddd, J ) 13.4, 6.3, 5.3 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 157.8, 150.2, 140.6, 129.0, 128.9,
127.8, 126.4, 123.2, 116.3, 82.4, 70.0, 62.3, 41.2, 40.2; HRMS
(DCI+ CH4) calcd for C18H19N2O3 [M + H+]; HRMS 311.1396,
found 311.1390.
trans-Ethyl 2-Benzyl-5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-
isoxazolidine-3-carboxylate (trans-5f). From 3b and 4a. The crude
mixture was purified from degradation products by chromatography
over silica gel (eluent ether, Rf ) 0.45). 310 mg (89%) after
procedure A and 334 mg (96%) after procedure B. An analytically
pure sample of trans adduct was obtained in the last fractions of
chromatography: pale yellow liquid; IR (neat) ν ) 1739, 1182,
1034; 1H NMR (400 MHz, CDCl3) δ 7.38-7.23 (m, 5H). 5.15 (dd,
J ) 8.5, 5.2 Hz, 1H), 4.18 (d, J ) 13.2 Hz, 1H), 4.14 (d, J ) 13.2
Hz, 1H), 4.06-4.14 (m, 2H), 4.02 (t, J ) 8.1 Hz, 1H), 4.00 (d, J
) 8.6 Hz, 1H), 3.95 (d, J ) 8.3 Hz, 1H), 3.36 (ddd, J5 ) 13.0, 8.1,
5.2 Hz, 1H), 2.64 (ddd, J ) 13.0, 8.5, 8.1 Hz, 1H), 1.29 (s, 6H),
1.23 (t, J) 7.1 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 170.2,
160.8, 136.5, 129.3, 128.0, 127.2, 80.9, 74.4, 66.3, 62.1, 61.1, 58.9,
34.6, 26.1, 25.4, 13.9; HRMS (DCI+ CH4) calcd for C18H25N2O5
[M + H+]; HRMS 349.1763, found 349.1762.
fication by flash chromatography (Et2O/cyclohexane 1:2 f 2/1)
afforded the title compound as a pale yellow oil: Rf ) 0.53 (diethyl
ether), 120 mg (10%); [R]23D ) +1.9 (c 2.75, chloroform); IR (KBr)
1
ν ) 2981, 1758, 1399, 1211, 1040 cm-1; H NMR (400 MHz,
CDCl3) δ 7.42-7.27 (m, 10H), 5.99 (dd, J ) 8.3, 5.3 Hz, 1H),
5.26 (dd, J ) 9.1, 4.8 Hz, 1H), 4.53 (dd, J ) 9.1, 8.6 Hz, 1H),
4.25 (d, J ) 13.6 Hz, 1H), 4.04 (dd, J ) 8.6, 4.8 Hz, 1H), 4.00-
3.93 (m, 2H), 3.91 (d, J ) 13.6 Hz, 1H), 3.41 (t, J ) 8.6 Hz, 1H),
2.47 (ddd, J ) 13.6, 8.6, 8.3 Hz, 1H), 2.09 (ddd, J ) 13.6, 8.6, 5.3
Hz, 1H), 1.12 (t, J ) 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
168.9, 158.8, 140.8, 136.2, 129.2, 128.9, 128.4, 128.2, 127.5, 126.7,
82.1, 71.0, 66.2, 61.5, 61.0, 56.2, 34.8, 13.8; HRMS (DCI +
methane) calcd for C22H25N2O5 [M + H+]; HRMS 397.1763, found
397.1773.
(3S,5R)-, (3R,5R)-, and (3S,5S)-Ethyl 2-Benzyl-5-((R)-4-phen-
yl-2-oxooxazolidin-3-yl)isoxazolidine-3-carboxylate ((3S,5R)-,
(3R,5R)-, and (3S,5S)-5i). From 3d and 4a. Purification by flash
chromatography (Et2O/cyclohexane 1:2 f 2/1) afforded the title
compound as a pale yellow oil nonseparable mixture ((3S,5R)/
(3S,5S)/(3R,5R) 1.0:2.5:1.0): Rf ) 0.48 (diethyl ether); 857 mg
(82%); IR (KBr) ν ) 2982, 1759, 1398, 1212, 1041 cm-1; some
characteristic NMR signals of (3S,5R) adduct 1H NMR (400 MHz,
CDCl3) δ 5.87 (dd, J ) 8.6, 4.8 Hz, 1H), 3.35-3.31 (m, 1H), 2.45
(ddd, J ) 13.1, 8.6, 7.1 Hz, 1H), 2.02 (ddd, J ) 13.1, 7.8, 4.8 Hz,
1H); some characteristic NMR signals of (3S,5S) adduct 1H NMR
(400 MHz, CDCl3) δ 5.11 (dd, J ) 8.1, 4.3 Hz, 1H), 3.93 (d, J )
13.3, 1H), 3.84 (t, J ) 7.8, 1H), 3.29 (ddd, J ) 12.9, 8.1, 4.3 Hz,
1H), 2.61 (ddd, J ) 12.9, 8.1, 7.3 Hz, 1H); 13C NMR (100 MHz
(CDCl3) δ 169.9, 156.2, 136.6, 82.9, 69.7, 65.8, 61.2, 60.2, 34.6,
14.0; some characteristic NMR signals of (3R,5R) adduct 1H NMR
(400 MHz, CDCl3) δ 5.38 (dd, J ) 7.3, 2.9 Hz, 1H), 3.44 (dd, J )
9.6, 7.2 Hz, 1H), 3.12 (ddd, J ) 13.6, 7.2, 2.9 Hz, 1H), 2.84 (ddd,
J ) 13.6, 9.6, 7.3 Hz, 1H).
3-(2-Benzyl-3-(4-(trifluoromethyl)phenyl)isoxazolidin-5-yl)-
4,4-dimethyloxazolidin-2-one (5g). From 3b and 4d. Purification
by flash chromatography (diethyl ether) afforded the title compound
as a colorless solid (nonseparable mixture, trans/cis 3.3:1): Rf )
0.45 (diethyl ether); 84 mg (20%) after procedure A and 345 mg
(82%) after procedure B; IR (KBr) ν ) 3032, 2973, 1759, 1325,
1165, 1123 cm-1; some characteristic NMR signals of major adduct
trans-5g 1H NMR (400 MHz, CDCl3) δ 7.62-7.57 (m, 4H). 7.27-
7.19 (m, 5H), 5.16 (dd, J ) 8.8, 4.0 Hz, 1H), 4.45 (dd, J ) 9.3,
7.6 Hz, 1H), 4.04 (d, J ) 8.2 Hz, 1H), 3.97 (d, J ) 8.2 Hz, 1H),
3.88 (s, 1H), 3.87 (s, 1H), 3.31 (ddd, J ) 12.6, 7.6; 4.0 Hz, 1H),
2.42 (ddd, J ) 12.6, 9.3, 8.8 Hz, 1H), 1.35 (s, 3H), 1.30 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 155.5, 143.5, 137.4, 128.2, 128.1,
(3S,5R)-Ethyl 2-Benzyl-5-((S)-4-ethyl-2-oxooxazolidin-3-yl)-
isoxazolidine-3-carboxylate ((3S,5R)-5j). From 3c and 4a. Puri-
fication by flash chromatography (Et2O/cyclohexane 1:2 f 2/1)
afforded the title compound as a pale yellow oil: Rf ) 0.64 (diethyl
ether), 113 mg (11%); [R]23 ) -83.5 (c 1.50, chloroform); IR
D
(KBr) ν ) 1748, 1404, 1219 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.37-7.27 (m, 5H), 5.90 (dd, J ) 8.3, 5.1 Hz, 1H), 4.25 (dd, J )
8.6, 8.3 Hz, 1H), 4.18 5d, J ) 13.6 Hz), 4.16 (q, J ) 7.1 Hz, 2H),
4.17-4.04 (m, 2H), 3.95 (dd, J ) 8.3, 5.6 Hz, 1H), 3.92 (d, J )
13.6 Hz, 1H), 2.90 (ddd, J ) 13.6, 8.5, 8.3 Hz, 1H), 2.67 (ddd, J
) 13.6, 9.1, 5.1 Hz, 1H), 2.13-2.03 (m, 1H), 1.79-1.68 (m, 1H),
1.27 (t, J ) 7.1 Hz, 3H), 0.89 (t, J ) 7.3 Hz, 3H); 13C NMR (100
MHz (CDCl3) δ 169.5, 158.8, 136.3, 129.1, 128.3, 127.6, 82.6,
67.7, 67.2, 61.6, 61.5, 53.7, 38.1, 26.3, 14.0, 8.1; HRMS (DCI +
methane) calcd for C18H25N2O5 [M + H+]; HRMS 349.1763, found
349.1775.
127.2, 125.6 (q, J3
) 4 Hz), 122.6 (q, J1
) 272 Hz), 80.3,
C-F
C-F
74.7, 69.2, 60.4, 59.1, 41.8, 26.4, 25.7; 19F NMR (376.5 MHz,
CDCl3) δ -62.5 (s, 3F); some characteristic NMR signals of minor
1
adduct cis-5e H NMR (400 MHz, CDCl3) δ 7.62-7.57 (m, 4H).
7.27-7.19 (m, 5H), 5.55 (dd, J ) 6.3, 7.8 Hz, 1H), 3.90 (s, 1H),
3.89 (s, 1H), 3.17 (ddd, J ) 13.1, 10.3; 6.3 Hz, 1H), 2.87 (ddd, J
) 13.1, 7.8, 7.1 Hz, 1H), 1.32 (s, 3H), 1.27 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 156.8, 143.5, 136.9, 128.4, 128.0, 127.2, 125.6
(q, J3
) 4 Hz), 122.6 (q, J1
) 272 Hz), 82.2, 75.1, 70.5,
C-F
C-F
60.1, 59.1, 41.8, 26.5, 25.5; 19F NMR (376.5 MHz, CDCl3) δ -62.6
(s, 3F); HRMS (DCI+ CH4) calcd for C22H24N2O3F3 [M + H+];
HRMS 421.1739, found 421.1754.
(3R,5S)-, (3R,5R)-, and (3S,5S)-Ethyl 2-Benzyl-5-((S)-4-eth-
yl-2-oxooxazolidin-3-yl)isoxazolidine-3-carboxylate ((3R,5S)-,
(3R,5R)-, and (3S,5S)-5j). From 3c and 4a. Purification by flash
chromatography (Et2O/cyclohexane 1:2 f 2/1) afforded the title
compound as a pale yellow oil non-separable mixture ((3R,5S)/
(3R,5R)/(3S,5S) 1.0:3.4:2.2): Rf ) 0.48 (diethyl ether); 857 mg
(82%); IR (KBr) ν ) 1748, 1404, 1219 cm-1; some charac-
teristic NMR signals of (3S,5R) adduct 1H NMR (400 MHz,
CDCl3) δ 5.92 (dd, J ) 7.8, 4.7 Hz, 1H), 3.56 (d, J ) 8.3
Hz, H), 0.70 (t, J ) 7.1 Hz, 3H); 13C NMR (100 MHz (CDCl3)
δ 169.9, 82.2, 61.5, 26.2, 14.0, 7.7; some characteristic NMR
signals of (3S,5S) adduct 1H NMR (400 MHz, CDCl3) δ 5.52 (dd,
J ) 7.8, 5.6 Hz, 1H), 0.81 (t, J ) 7.1 Hz, 3H); 13C NMR (100
MHz (CDCl3) δ 169.8, 82.4, 61.3, 25.6, 14.0, 7.7; some charac-
teristic NMR signals of (3R,5R) adduct 1H NMR (400 MHz,
CDCl3) δ δ 5.40 (dd, J ) 7.3, 5.3 Hz, 1H), 0.86 (t, J ) 7.1 Hz,
3H); 13C NMR (100 MHz (CDCl3) δ 169.7, 83.8, 61.8, 26.5,
14.0, 7.8.
Ethyl 2-Benzyl-4-methyl-5-(2-oxooxazolidin-3-yl)isoxazolidine-
3-carboxylate (trans-5h). From 3g and 4a. The crude mixture was
purified from degradation products by chromatography on silica
gel (CH2Cl2 f CH2Cl2/Et2O 1:1) to afford trans-5h (Rf ) 0.45,
diethyl ether). 167 mg (50%) after procedure A and 234 mg (70%)
after procedure B (another less polar adduct could not be separated
from degradation products): pale yellow liquid; IR ν ) 2931, 1748,
1
1253, 1193 cm-1; H NMR (400 MHz, CDCl3) δ 7.38-7.26 (m,
5H), 5.80 (d, J ) 7.8, 1H), 4.29 (dd, J ) 7.3, 8.6 Hz, 2H), 4.17 (d,
J ) 13.4, 1H), 4.11 (m, 2H), 4.10 (d, J ) 13.4, 1H), 3.61 (∼q, J
) 8.3 Hz, 1H), 3.42 (∼q, J ) 8.3 Hz, 1H), 3.28 (d, J ) 10.3 Hz,
1H), 3.15 (m, 1H), 1.24 (t, J ) 7.1 Hz, 3H), 1.12 (d, J ) 7.1 Hz,
3H); 13C NMR (100 MHz (CDCl3) δ 168.8, 157.8, 135.1, 129.6,
128.2, 127.8, 84.7, 72.0, 62.1, 61.5, 44.6, 41.9, 14.0, 11.0; HRMS
(DCI+ CH4) calcd for C17H23N2O5 [M + H+]; HRMS 335.1607,
found 335.1593.
(3R,5S)-Ethyl 2-Benzyl-5-((R)-4-phenyl-2-oxooxazolidin-3-yl)-
isoxazolidine-3-carboxylate ((3R,5S)-5i). From 3d and 4a. Puri-
(2R,3aR,7R)-2-(2-Oxooxazolidin-3-yl)-7-phenyltetrahydroisox-
azolo[3,2-c][1,4]oxazin-4(2H)-one (6). From 3a and 4f after
J. Org. Chem, Vol. 73, No. 7, 2008 2629

Nguyen et al.
procedure B. The crude mixture was purified from degradation
products by chromatography over silica gel (eluent ether, Rf ) 0.4)
to afford 289 mg of the title compound (97%) as a mixture of two
diastereomers (86:14 ratio): pale yellow oil; ν ) 2972, 1743, 1340,
Na2CO3 aqueous solution (20 mL). The organic phase was sepa-
rated, dried (MgSO4), and concentrated under reduced pressure.
The oily residue was purified by chromatography on silica gel
(CH2Cl2).
1
1223, 1040 cm-1; H NMR (400 MHz, CDCl3) major isomer δ
Ethyl 2-(Dibenzylamino)-4-oxo-4-(2-oxooxazolidin-3-yl)bu-
tanoate (10a). From 320 mg of 5a, 377 mg (92%) of 10a was
obtained as an off-white solid: Rf ) 0.3 (dichloromethane); mp )
139-140 °C (dichloromethane); IR (KBr) ν ) 3062, 3028, 2982,
7.43-7.32 (m, 5H), 5.94 (dd, J ) 8.3, 3.0 Hz, 1H), 4.43-4.27 (m,
5H), 4.18 (dd, J ) 9.9, 3.8 Hz, 1H), 3.81-3.75 (m, 1H), 3.67-
3.61 (m, 1H), 3.09 (ddd, J ) 14.1, 8.3, 7.5 Hz, 1H), 2.76 (ddd, J
) 14.1, 8.8, 3.0 Hz, 1H); characteristic signal of the minor isomer
6.01 (dd, J ) 7.3, 3.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
168.7, 157.0, 135.0, 128.5, 128.3, 127.1, 81.3, 69.0, 62.7, 61.9,
60.6, 39.8, 34.4; HRMS (DCI+ CH4) calcd for C15H17N2O5 [M +
H+]; HRMS 305.1137, found 305.1140.
1
2926, 2848, 1775, 1728, 1391, 1221 cm-1; H NMR (400 MHz,
CDCl3) δ 7.43-7.36 (m, 4H), 7.31-7.27 (m, 4H), 7.24-7.20 (m,
2H), 4.34-4.14 (m, 4H), 3.97 (dd, J ) 8.3, 6.7 Hz, 1H), 3.87-
3.74 (m, 2H), 3.83 (d, J ) 13.6 Hz, 2H), 3.59 (dd, J ) 16.2, 8.3
Hz, 1H), 3.57 (d, J ) 13.6 Hz, 2H), 3.08 (dd, J ) 16.2, 6.7 Hz,
1H), 1.36 (t, J ) 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) 171.4,
170.7, 153.1, 139.1, 129.0, 128.2, 127.0, 61.9, 60.7, 57.3, 54.7,
42.2, 35.8, 14.5; HRMS (DCI+ CH4) calcd for [M + H+];
HRMSC23H27N2O5 411.1920, found 411.1917.
(2R,3aR,7R)-2-(4,4-Dimethyl-2-oxooxazolidin-3-yl)-7-phenyltet-
rahydroisoxazolo[3,2-c][1,4]oxazin-4-(2H)-one (7). From 3b and
4f after procedure B. The crude mixture was purified from
degradation products by chromatography over silica gel (eluent
diethyl ether, Rf ) 0.3) to afford 312 mg of the title compound
(94%) as colorless crystals: mp 189-191 °C; [R]23D ) -170.0 (c
1.00, chloroform); IR (KBr) ν ) 2973, 1742, 1341, 1225, 1041
Ethyl 2-(Dibenzylamino)-4-(4,4-dimethyl-2-oxooxazolidin-3-
yl)-4-oxobutanoate (10b). From 348 mg of 5f, 394 mg (90%) of
10b was obtained as a colorless oil: Rf ) 0.3 (dichloromethane);
IR (KBr) ν ) 2980, 2928, 2910, 1780, 1721, 1699, 1383, 1329,
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.46-7.44 (m, 2H), 7.40-
1
1179, 1096 cm-1; H NMR (400 MHz, CDCl3) δ 7.37-7.35 (m,
7.31 (m, 3H), 5.19 (dd, J ) 8.6, 2.8 Hz, 1H), 4.90 (t, J ) 8.3 Hz,
1H), 4.30 (dd, J ) 11.9, 4.0 Hz, 1H), 4.23 (dd, J ) 11.9, 10.4 Hz,
1H), 4.08 (dd, J ) 10.4, 4.0 Hz, 1H), 3.96 (d, J ) 8.3 Hz, 1H),
3.92 (d, J ) 8.3 Hz, 1H), 3.41 (ddd, J ) 13.4, 9.1, 2.5 Hz, 1H),
2.96 (ddd, J ) 13.4, 8.6, 8.1 Hz, 1H), 1.18 (s, 3H), 1.30 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 170.0, 155.2, 136.6, 129.3, 128.0,
127.3, 81.0, 74.5, 66.3, 62.1, 61.1, 59.0, 34.6, 26.1, 25.5, 13.9;
HRMS (DCI+ CH4) calcd for C17H21N2O5 [M + H+]; HRMS
333.1450, found 333.1454.
4H), 7.31-7.28 (m, 4H), 7.25-7.21 (m, 2H), 4.34-4.17 (m, 2H),
3.98 (dd, J ) 9.6, 5.3 Hz, 1H), 3.94 (d, J ) 8.3 Hz, 1H), 3.92 (d,
J ) 8.3 Hz, 1H), 3.82 (d, J ) 13.9 Hz, 2H), 3.60 (d, J ) 13.9 Hz,
2H), 3.59 (dd, J ) 17.2, 9.3 Hz, 1H), 3.10 (dd, J ) 17.2, 5.6 Hz,
1H), 1.50 (s, 6H), 1.36 (t, J ) 7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3) 171.7, 171.5, 153.9, 139.1, 128.8, 128.2, 127.0, 75.1, 60.5,
60.2, 57.5, 54.9, 37.1, 24.8, 24.4, 14.5; HRMS (DCI+ CH4) calcd
for [M + H+]; HRMSC25H31N2O5:439.2233, found 439.2238.
(S)-Ethyl 2-(Dibenzylamino)-4-((R)-4-phenyl-2-oxooxazolidin-
3-yl)-4-oxobutanoate ((4′R,3S)-10c). From 198 mg of (3S,5R)-,
(3R,5R)-, and (3S,5S)-5i as a mixture of three nonseparable
diastereomers, 167 mg (69%) of (R,S)-10c was obtained as a pale
yellow oil: Rf ) 0.25 (dichloromethane); [R]23D ) -113.6 (c 1.20,
chloroform); IR (KBr) ν ) 3062, 3029, 2979, 2931, 2844, 1781,
(2R,3aR,7R)-2-(2-Oxopyrrolidin-1-yl)-7-phenyltetrahydroisox-
azolo[3,2-c][1,4]oxazin-4(2H)-one (8). From 3m and 4f. After
procedure B, the crude mixture was purified from degradation
products by chromatography over silica gel (eluent ether, Rf ) 0.4)
to afford 281 mg of the title compound (93%) as a mixture of two
diastereomers (88:12 ratio): pale yellow liquid; IR (KBr) ν ) 2957,
1751, 1686, 1420, 1288, 1231 cm-1; 1H NMR (400 MHz, CDCl3)
major isomer δ 7.43-7.32 (m, 5H), 6.16 (dd, J ) 8.6, 3.3 Hz,
1H), 4.44 (dd, J ) 8.8, 8.3 Hz, 1H), 4.33 (dd, J ) 11.9, 3.8 Hz,
1H), 4.25 (dd, J ) 11.9, 10.4 Hz, 1H), 4.14 (dd, J ) 10.1, 3.8 Hz,
1H), 3.58-3.51 (m, 1H), 3.47-3.36 (m, 1H), 2.98 (ddd, J ) 13.9,
8.6, 8.3 Hz, 1H), 2.66 (ddd, J ) 13.9, 8.8, 3.3 Hz, 1H), 2.40-2.26
(m, 2H), 2.05-1.94 (m, 2H); characteristic signal of the minor
isomer 6.18 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 175.4, 168.6,
134.9, 128.7, 128.5, 127.4, 79.1, 69.5, 62.4, 61.4, 42.0, 34.8, 31.0,
17.6; HRMS (DCI+ CH4) calcd for C16H19N2O4 [M + H+]; HRMS
303.1345, found 303.1340.
1
1385, 1205 cm-1; H NMR (400 MHz, CDCl3) δ 7.37-7.19 (m,
15H), 5.32 (dd, J ) 8.6, 4.1 Hz, 1H), 4.61 (dd, J ) 8.8, 8.6 Hz,
1H), 4.22 (dd, J ) 8.8, 4.1 Hz, 1H), 4.16-4.01 (m, 2H), 3.94 (dd,
J ) 9.9, 4.5 Hz, 1H), 3.81 (d, J ) 13.9 Hz, 2H), 3.70 (dd, J )
17.7, 10.0 Hz, 1H), 3.59 (d, J ) 13.9 Hz, 2H), 3.15 (dd, J ) 17.7,
4.5 Hz, 1H), 1.17 (t, J ) 7.1 Hz, 3H; 13C NMR (100 MHz, CDCl3)
171.2, 170.4, 153.6, 139.1, 138.6, 129.1, 128.7, 128.6, 128.3, 127.1,
125.8, 70.0, 60.5, 57.6, 57.5, 55.0, 39.4, 14.3; HRMS (DCI-) calcd
for [M]; HRMSC29H30N2O5 486.2155, found 486.2158.
(R)-Ethyl 2-(Dibenzylamino)-4-((R)-4-phenyl-2-oxooxazolidin-
3-yl)-4-oxobutanoate ((4′R,3R)-10c). From 174 mg of (3S,5R)-,
(3R,5R)-, and (3S,5S)-5i as a mixture of 3 non-separable diaster-
eomers, 50 mg (21%) of (R,R)-10c was obtained as a pale yellow
2-((2R,3aR,7R)-4-Oxo-7-phenylhexahydroisoxazolo[3,2-c][1,4]-
oxazin-2-yl)isoindoline-1,3-dione (9). From 3f and 4f. After
procedure B, the crude mixture was purified from degradation
products by recrystallization (toluene) to afford 317 mg of the title
compound (87%) as colorless crystals:mp 210-212 °C (dichlo-
oil: Rf ) 0.16 (dichloromethane); [R]23 ) +0.1 (c 0.91,
D
chloroform); IR (KBr) ν ) 3062, 3029, 2980, 2928, 2845, 1770,
1
1385, 1181 cm-1; H NMR (400 MHz, CDCl3) δ 7.38-7.20 (m,
romethane); [R]23 ) -146.8 (c 0.70, chloroform); IR (KBr) ν )
15H), 5.27 (dd, J ) 8.6, 3.3 Hz, 1H), 4.55 (dd, J ) 8.8, 8.6 Hz,
1H), 4.20 (dd, J ) 8.8, 3.3 Hz, 1H), 4.33-4.15 (m, 2H), 3.92 (dd,
J ) 8.6, 6.3 Hz, 1H), 3.79 (d, J ) 13.9 Hz, 2H), 3.68 (dd, J )
16.7, 8.6 Hz, 1H), 3.56 (d, J ) 13.6 Hz, 2H), 3.07 (dd, J ) 16.7,
6.3 Hz, 1H), 1.35 (t, J ) 7.1 Hz, 3H; 13C NMR (100 MHz, CDCl3)
δ 171.6, 170.1, 153.5, 139.1, 139.0, 129.1, 128.9, 128.7, 128.2,
127.0, 125.9, 70.0, 60.7, 57.47, 57.44, 54.8, 35.8, 14.5.
D
1
2945, 1775, 1749, 1722, 1363, 1234 cm-1; H NMR (400 MHz,
CDCl3) δ 7.86 (dd, J ) 5.6, 3.3 Hz, 2H), 7.75 (dd, J ) 5.6, 3.3
Hz, 2H), 7.45-7.42 (m, 2H), 7.37-7.30 (m, 3H), 6.19 (dd, J )
8.8, 2.5 Hz, 1H), 5.15 (t, J ) 8.8 Hz, 1H), 4.34 (dd, J ) 7.8, 4.0
Hz, 1H), 4.29 (dd, J ) 11.0, 7.8 Hz, 1H), 4.15 (dd, J ) 11.0, 4.0
Hz, 1H), 3.32 (ddd, J ) 13.6, 9.1, 2.5 Hz, 1H), 3.14 (ddd, J )
13.6, 9.1, 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.3, 167.1,
135.1, 134.5, 131.5, 128.8, 128.6, 127.4, 123.6, 100.0, 69.8, 63.3,
61.6, 35.8; HRMS (DCI+ CH4) calcd for C20H17N2O5 [M + H+];
HRMS 365.1137, found 365.1159.
General Procedure for Preparation of 10a and 10b. Com-
pound 5a, 5f, 5i, or 5j (either a single isomer or a mixture could
be used) (1 mmol) was heated at 50 °C for 3 d with benzyl bromide
(3 equiv). Excess benzyl bromide was removed by distillation under
vacuum (short path distillation apparatus, 50 °C, 0,01 mmHg). The
solid residue was dissolved in Et2O (100 mL) and treated with 5%
(R)-Ethyl 2-(Dibenzylamino)-4-((S)-4-ethyl-2-oxooxazolidin-
3-yl)-4-oxobutanoate ((4′S,3R)-10d). From 174 mg of (3R,5S)-,
(3R,5R)-, and (3S,5S)-5i as a mixture of three nonseparable
diastereomers, 116 mg (53%) of (S,R)-10d was obtained as a pale
yellow oil: Rf ) 0.24 (dichloromethane); [R]23D ) +24.6 (c 1.30,
chloroform); IR (KBr) ν ) 2976, 1780, 1726, 1391, 1209 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.37-7.35 (m, 4H), 7.31-7.27 (m,
4H), 7.23-7.19 (m, 2H), 4.34-4.16 (m, 4H), 4.04-3.93 (m, 2H),
3.83 (d, J ) 13.6 Hz, 2H), 3.70-3.57 (m, 3H), 3.10 (dd, J ) 17.4,
5.1 Hz, 1H), 1.81-1.70 (m, 1H), 1.68-1.56 (m, 1H), 1.38-1.32
2630 J. Org. Chem., Vol. 73, No. 7, 2008

1,3-Dipolar Cycloaddition of Dipolarophiles and Nitrones
(m, 3H), 0.86-0.82 (m, 3H); 13C NMR (100 MHz, CDCl3) 171.4,
170.6, 153.5, 139.0, 128.8, 128.2, 127.0, 66.7, 60.5, 57.4, 54.9,
54.8, 35.8, 14.5, 8.1; HRMS (DCI + methane) calcd for [M +
H+]; HRMS C25H31N2O5 439.2233, found 439.2254.
1H), 1.36 (t, J ) 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) 171.3,
171.3, 138.9, 128.8, 128.2, 127.1, 61.1, 57.8, 54.6, 51.5, 34.9, 14.4;
HRMS (DCI+ CH4) calcd for [M + H+]; HRMS C21H26NO4
356.1862, found 356.1862.
(S)-Ethyl 2-(Dibenzylamino)-4-((S)-4-ethyl-2-oxooxazolidin-
3-yl)-4-oxobutanoate ((4′S,3S)-10d). From 174 mg of (3R,5S)-,
(3R,5R)-, and (3S,5S)-5i as a mixture of three nonseparable
diastereomers, 91 mg (42%) of (S,S)-10d was obtained as a
1-Ethyl 2-(Dibenzylamino)-4-(methoxy(methyl)amino)-4-oxo-
butanoate (14). To a well-stirred solution of 10a (41.0 mg, 0.1
mmol) and Weinreb’s amine hydrochloride salt CH3ONHCH3‚HCl
(29.3 mg, 0.3 mmol) under argon in dichloromethane (0.5 mL) was
injected AlMe3 (2 M in hexanes, 150 µL, 1 mmol) at room
temperature. The mixture was stirred for 30 h, and then the solvent
was evaporated under reduced pressure. The residue was flash
chromatographed (diethyl ether, Rf ) 0.4) to give the title compound
(32.1 mg, 95%) as a pale yellow oil: IR (KBr) ν ) 2927, 1728,
1664, 1454, 1177, 1028 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.39-
7.37 (m, 4H), 7.32-7.28 (m, 4H), 7.25-7.20 (m, 2H), 4.35-4.17
(m, 2H), 3.94 (dd, J ) 9.9, 5.1 Hz, 1H), 3.84 (d, J ) 13.9 Hz,
2H), 3.61 (d, J ) 13.9 Hz, 2H), 3.61 (s, 3H), 3.10, (s, 3H), 3.14-
3.01 (m, 1H), 2.64-2.59 (m, 1H), 1.37 (t, J ) 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) 171.9, 171.8, 139.3, 128.7, 128.2, 127.0,
61.0, 60.5, 57.8, 55.1, 32.7, 14.5; HRMS (FI) calcd for C22H28N2O4
384.2049, found 384.2048.
Ethyl 4-(Butylamino)-2-(dibenzylamino)-4-oxobutanoate (15).
A mixture of 10a (41.0 mg, 0.1 mmol) and n-butylamine (73 mg,
1 mmol) was stirred for 10 min at room temperature, and then the
n-butylamine in excess was evaporated under reduced pressure. The
residue was flash chromatographed (diethyl ether, Rf ) 0.45) to
give the title compound (37.6 mg, 90%) as a colorless yellow oil:
IR (KBr) ν ) 2924, 1721, 1663, 1452, 1177 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.34-7.24 (m, 10H), 6.38 (br b., 1H), 4.34-4.19
(m, 2H), 3.91 (d, J ) 13.6 Hz, 2H), 3.83 (dd, J ) 8.6, 6.1, 1H),
3.60 (d, J ) 13.6 Hz, 2H), 3.21-3.13 (m, 1H), 3.04-2.96 (m,
1H), 2.69-2.57 (m, 2H), 1.41-1.33 (m, 2H), 1.36 (t, J ) 7.1 Hz,
3H); 1.33-1.24 (m, 2H), 0.91 (t, J ) 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 171.3, 170.0, 138.5, 129.1, 128.4, 127.4, 60.7,
58.2, 54.7, 39.0, 35.8, 32.6, 20.1, 14.5, 13.7; HRMS (DCI+
CH4) calcd for [M + H+]; HRMS C24H33N2O3 397.2491, found
397.2499.
pale yellow oil: Rf ) 0.14 (dichloromethane); [R]23 ) -13.2 (c
D
1.05, chloroform); IR (KBr) ν ) 2975, 1781, 1726, 1392, 1207
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.37-7.35 (m, 4H), 7.33-
7.27 (m, 4H), 7.25-7.21 (m, 2H), 4.35-4.18 (m, 4H), 4.04 (dd,
J ) 8.0, 2.1 Hz, 1H), 3.95 (dd, J ) 8.8, 5.8 Hz, 1H), 3.83 (d,
J ) 13.6 Hz, 2H), 3.63 (dd, J ) 16.7, 8.8 Hz, 1H), 3.57 (d,
J ) 13.6 Hz, 2H), 3.09 (dd, J ) 16.7, 5.8 Hz, 1H), 1.83-1.75
(m, 1H), 1.71-1.61 (m, 1H), 1.38 (t, J ) 7.1 Hz, 3H), 0.87 (t, J )
7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) 171.5, 170.6, 153.5,
139.1, 128.9, 128.2, 127.1, 66.7, 60.7, 57.4, 55.1, 54.8, 36.0, 25.0,
14.5, 8.1.
3-(Dibenzylamino)-4-ethoxy-4-oxobutanoic Acid (11). A mix-
ture of 10a or 10b (0.1 mmol) and LiOH (12 mg, 0.5 mmol) in
H2O (0.5 mL) and THF (0.5 mL) was stirred at room temperature
for 30 min. The reaction was quenched with HCOOH (50 µL) and
extracted with dichloromethane (20 mL). The organic layer was
washed with brine, dried over MgSO4, and evaporated. The residue
was purified by column chromatography (silica gel, dichlo-
romethane to dichloromethane:diethyl ether 1:1) to afford acid 11
(27.2 mg (80%) from 10a, 29.1 mg (85%) from 10b) as a pale
yellow oil: Rf ) 0.5 (dichloromethane:diethyl ether 1:1); IR (KBr)
ν ) 3433, 2925, 1735 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.33-
7.32 (m, 8H), 7.30-7.25 (m, 2H), 4.36-4.22 (m, 2H), 3.94 (d, J
) 13.1 Hz, 2H), 3.85 (t, J ) 7.8 Hz, 1H), 3.62 (d, J ) 13.1 Hz,
2H), 2.79 (d, J ) 7.8 Hz, 2H), 1.38 (t, J ) 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) 174.2, 170.2, 137.1, 129.3, 128.6, 127.7, 61.1,
57.0, 54.6, 33.5, 14.4; HRMS (FI) calcd for [M + H+]; HRMS
C20H24NO4 342.1705, found 342.1688.
4-Benzyl 1-Ethyl 2-(Dibenzylamino)succinate (12). To a well-
stirred solution of benzyl alcohol (21.6 mg, 0.2 mmol) in THF (0.5
mL) was added n-BuLi (1.6 M in hexane, 94 µL, 0.15 mmol) at
room temperature. The solution was stirred for 30 min, and then a
solution of 10a (41.0 mg, 0.1 mmol) in THF (1 mL) was added.
After 30 min of additional stirring, the reaction was quenched with
HCOOH (50 µL) and extracted with dichloromethane (20 mL). The
organic layer was washed with brine, dried over MgSO4, and
evaporated. The residue was purified by column chromatography
(silica gel, dichloromethane) to afford diester 12 (32.8 mg, 76%)
as a pale yellow oil: Rf ) 0.6 (diethyl ether); IR (KBr) ν ) 3063,
3030, 2981, 1732, 1165, 1027 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.34-7.20 (m, 15H), 5.13 (d, J ) 12.4 Hz, 1H), 4.93 (d, J )
12.4 Hz, 1H), 4.30-4.15 (m, 2H), 3.91 (dd, J ) 8.1, 7.1 Hz, 1H),
3.82 (d, J ) 13.6 Hz, 2H), 3.57 (d, J ) 13.6 Hz, 2H), 2.92 (dd, J
) 15.7, 8.1 Hz, 1H), 2.71 (dd, J ) 15.7, 7.1 Hz, 1H), 1.36 (t, J )
7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) 171.4, 170.9, 138.9,
135.7, 128.9, 128. 5, 128.3, 128.23, 128.19, 127.1, 66.4, 60.7, 58.0,
54.8, 51.5, 35.2, 14.5; HRMS (FD) calcd for C27H29NO4 431.2097,
found 431.2137.
Ethyl 2-(Dibenzylamino)-4-(2-methoxy-2-oxoethylamino)-4-
oxobutanoate (16). To a well-stirred solution of 10a (41.0 mg,
0.1 mmol) and NH2CH2COOCH3‚HCl (37.7 mg, 0.3 mmol) under
argon in dichloromethane (0.5 mL) was injected AlMe3 (2 M in
hexanes, 150 µL, 1 mmol) at room temperature. The mixture was
stirred for 2 h, and then the solvent was evaporated under reduced
pressure. The residue was flash chromatographed (dichloromethane/
diethyl ether 9:1, Rf ) 0.3) to give the dipeptide 16 (30.1 mg, 79%)
as a pale yellow oil: IR (KBr) ν ) 3323, 3029, 2953, 2848, 1728,
1
1655, 1542, 1454, 1371, 1209, 1178, 1028 cm-1; H NMR (400
MHz, CDCl3) δ 7.35-7.23 (m, 10H), 6.82 (br, 1H), 4.35-4.20
(m, 2H), 3.97 (dd, J ) 18.2, 5.8 Hz, 1H), 3.90 (d, J ) 13.6 Hz,
2H), 3.85 (d, J ) 7.1 Hz, 1H), 3.74 (s, 3H), 3.73 (dd, J ) 18.2,
5.1, 1H), 3.60 (d, J ) 13.6 Hz, 2H), 2.69 (d, J ) 7.1 Hz, 2H), 1.37
(t, J ) 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.2, 170.4,
170.1, 138.5, 129.2, 128.4, 127.4, 60.8, 58.1, 52.2, 44.8, 41.0, 35.6,
14.5; HRMS (DCI+ CH4) calcd for [M + H+]; HRMS C23H29N2O5
413.2076, found 413.2089.
3-(Dibenzylamino)-1-(2-hydroxyethyl)pyrrolidine-2,5-dione (17).
To a well-stirred solution of 10a (41.0 mg, 0.1 mmol) in THF (0.5
mL) was added ethanolamine (61 mg, 1 mmol) at room temperature.
The mixture was stirred for 2 h, and then the solvent was evaporated
under reduced pressure. The residue was flash chromatographed
(diethyl ether, Rf ) 0.4) to give the succinimide 18 (32.2 mg, 95%)
as a pale yellow oil: IR (KBr) ν ) 3454, 3028, 1699, 1398, 1028
1-Ethyl 4-Methyl 2-(Dibenzylamino)succinate (13). A solution
of 10a (41.0 mg, 0.1 mmol) and NaOCH3 (16.2 mg, 0.3 mmol) in
CH3OH (1 mL) was stirred for 30 min at room temperature. The
reaction was quenched with HCOOH (50 µL) and extracted with
dichloromethane (20 mL). The organic layer was washed with brine,
dried over MgSO4, and evaporated. The residue was purified by
column chromatography (silica gel, diethyl ether) to afford diester
13 (32.0 mg, 90%) as a pale yellow oil: Rf ) 0.9 (diethyl ether);
IR (KBr) ν ) 3063, 3029, 2983, 2952, 2847, 1732, 1454, 1169,
1
cm-1. H NMR (400 MHz, CDCl3) δ 7.41-7.38 (m, 4H), 7.35-
7.30 (m, 4H), 7.28-7.24 (m, 2H), 3.97 (dd, J ) 9.1, 5.3 Hz, 1H),
3.83 (d, J ) 13.4 Hz, 2H), 3.77-3.73 (m, Hz, 2H), 3.71-3.68 (m,
2H), 3.65 (d, J ) 13.4 Hz, 2H), 2.78 (dd, J ) 18.5, 9.1 Hz, 1H),
2.65 (dd, J ) 18.5, 5.3 Hz, 1H), 2.21 (br, 1H); 13C NMR (100
MHz, CDCl3) δ 178.0, 175.9, 138.2, 128.8, 128.5, 127.6, 60.5, 57.5,
1
1027 cm-1; H NMR (400 MHz, CDCl3) δ 7.35-7.28 (m, 8H),
7.26-7.21 (m, 2H), 4.34-4.17 (m, 2H), 3.87 (dd, J ) 7.8, 7.4 Hz,
1H), 3.83 (d, J ) 13.6 Hz, 2H), 3.58 (s, 3H), 3.57 (d, J ) 13.6 Hz,
2H), 2.85 (dd, J ) 15.4, 7.8 Hz, 1H), 2.67 (dd, J ) 15.4, 7.4 Hz,
J. Org. Chem, Vol. 73, No. 7, 2008 2631

Nguyen et al.
sample of (S)-18 was prepared from L-aspartic acid:32 [R]23
54.7, 41.3, 32.1, 30.3; HRMS (FI) calcd for [M + H+]; HRMS
C20H22N2O3 338.1630, found 338.1651.
)
D
-110.3 (c 2.05, chloroform).
(S)-Diethyl 2-(Dibenzylamino)succinate (S)-18. A solution of
(3S)-10c (48.6 mg, 0.10 mmol) and NaOC2H5 (6.8 mg, 0.1 mmol)
in EtOH (1 mL) was stirred for 30 min at room temperature. The
reaction was quenched with HCOOH (50 µL) and extracted with
dichloromethane (20 mL). The organic layer was washed with brine,
dried over MgSO4, and evaporated. The residue was purified by
column chromatography (silica gel, diethyl ether) to afford diester
(S)-18 (26.2 mg, 66%) as a pale yellow oil: Rf ) 0.91 (diethyl
ether); [R]23D ) -112.4 (c 1.31, chloroform); IR (KBr) ν ) 3062,
2951, 1733, 1454 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.35-7.33
(m, 4H), 7.32-7.28 (m, 4H), 7.25-7.21 (m, 2H), 4.33-4.18 (m,
2H), 4.16-4.06 (m, 1H), 4.03-3.95 (m, 1H), 3.87 (dd, J ) 7.3,
8.1 Hz, 1H), 3.83 (d, J ) 13.6 Hz, 2H), 3.58 (d, J ) 13.6 Hz, 2H),
2.85 (dd, J ) 15.7, 8.1 Hz, 1H), 2.65 (dd, J ) 15.7, 7.3 Hz, 1H),
1.36 (t, J ) 7.1 Hz, 3H), 1.17 (t, J ) 7.1 Hz, 3H). An authentical
(R)-Diethyl 2-(Dibenzylamino)succinate (R)-18. (3R)-10d (43.8
mg, 0.10 mmol), submitted to the same treatment as for (R,S)-10c,
afforded (R)-18 as a pale yellow oil (28.0 mg, 76%): [R]23
+113.7 (c 1.56, chloroform).
)
D
Acknowledgment. We thank the French Ministry of Re-
search for T.B.N.’s PhD grant.
Supporting Information Available: NMR spectroscopic data
for all new compounds 3-17. This material is available free of
charge via the Internet at http://pubs.acs.org.
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