Competitive formation of β-enaminones and 3-amino-2(5H)-furanones from the isoxazolidine system: A combined synthetic and quantum chemical study

Article abstract of DOI:10.1002/ejoc.201000579

Treatment of 3-alkoxycarbonyl-4-acyl- or 3,4-dialkoxycarbonyl-substituted isoxazolidines with a mild base, such as tetrabutylammonium fluoride, affords β-enaminones and/or 3-methylamino-2(5H)-furanones according to the nature of the substituents at C⁴ and C⁵. Two alternative mechanisms (lactonization and retro-aldolization) have been rationalized by DFT quantum chemical methods. Any realistic theoretical modeling requires the explicit inclusion of countercation and solvent effects. Substituted isoxazolidines afford β-enaminones and/or 3-methylamino-2(5H)-furanones by treatment with tetrabutylammonium fluoride according to the nature of the substituents at C⁴ and C⁵. Two alternative mechanisms (lactonization and retroaldolization) have been rationalized by DFT quantum chemical methods.

Full text of DOI:10.1002/ejoc.201000579

FULL PAPER
DOI: 10.1002/ejoc.201000579
Competitive Formation of β-Enaminones and 3-Amino-2(5H)-furanones from
the Isoxazolidine System: A Combined Synthetic and Quantum Chemical
Study
Daniela Iannazzo,*[a] Elisa Brunaccini,[a] Salvatore V. Giofrè,[a] Anna Piperno,[a]
Giovanni Romeo,[a] Simone Ronsisvalle,[b] Maria A. Chiacchio,[c] Giuseppe Lanza,*[c] and
Ugo Chiacchio[c]
Dedicated to Professor Saverio Florio on the occasion of his 70th birthday
Keywords: 1,3-Dipolar cycloaddition / Density function calculations / Isoxazolidines / β-Enaminones / 2(5H)-Furanones
Treatment of 3-alkoxycarbonyl-4-acyl- or 3,4-dialkoxycarb-
onyl-substituted isoxazolidines with a mild base, such as tet-
rabutylammonium fluoride, affords β-enaminones and/or 3-
methylamino-2(5H)-furanones according to the nature of the
substituents at C4 and C5. Two alternative mechanisms (lac-
tonization and retro-aldolization) have been rationalized by
DFT quantum chemical methods. Any realistic theoretical
modeling requires the explicit inclusion of countercation and
solvent effects.
furanones 4 has been performed by using a mild base, such
as tetrabutylammonium fluoride (TBAF), in 75–85% yield.
Compounds 4, which can be considered as diketo acid cy-
clic analogues, have shown very interesting biological prop-
erties as inhibitors of subgenomic hepatitis C virus RNA
replication.[5] The driving force for this kind of rearrange-
ment is represented by the low critical energy required to
induce an anionic centre at the C3 position of the isoxazoli-
dine nucleus, which promotes the ring opening of the
heterocyclic system and the subsequent intramolecular lac-
tonization.[4,5]
Introduction
Isoxazolidines, easily accessible through the 1,3-dipolar
cycloaddition of nitrones to substituted alkenes are valuable
synthons for the production of simple and complex mole-
cules.[1] The ring opening of these heterocycles allows a fac-
ile access to a variety of functionalized intermediates, such
as 1,3-amino alcohols, α,β-enones, tetrahydro-1,3-oxazines,
N-substituted hydroxylamines, 1,3-amino-ketones, polysub-
stituted allylic alcohols, and γ- and δ-lactams (Figure 1).[2]
In particular, the basic treatment of isoxazolidines suitably
activated at the 3-position of the pentatomic ring has been
exploited for a general synthetic approach to 3-alkylamino-
2(5H)-furanones, versatile synthons for β-lactams.[3] Thus,
3-alkoxycarbonyl-substituted isoxazolidines 1 undergo re-
arrangement to furanones 2 after treatment with NaH at
room temperature (Figure 2).[4] Recently, the chemical con-
version of 3-alkoxycarbonyl-4-acyl- or 3,4-dialkoxycarb-
onyl-substituted isoxazolidines 3 to 3-alkylamino-2(5H)-
[a] Dipartimento Farmaco-Chimico, Università di Messina,
Via SS. Annunziata, 98168 Messina, Italy
Fax: +39-0906766562
E-mail: diannazzo@unime.it
[b] Dipartimento di Scienze Farmaceutiche, Università di Catania,
Viale A. Doria, 6 95125 Catania, Italy
Fax: +39-095222239
[c] Dipartimento di Scienze Chimiche, Università di Catania,
Viale A. Doria 6, 95125 Catania, Italy
Fax: +39-095580138
E-mail: glanza@unict.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000579.
Figure 1. Ring-opening reactions of isoxazolidines.
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D. Iannazzo, G. Lanza et al.
Table 1. Cycloaddition between nitrone 6 and alkenes 7–9.
FULL PAPER
Entry[a] Alkene Lewis acid
Product
a/b/c/d
yield [%][b]
(ratio)[c]
1
2
3
4
5
7
8
8
9
9
none
none
ATPH
none
ATPH
10 (85)
11 (20)
11 (86)
12 (20)
12 (85)
4.5:1:0:0
2:1:0.4:0.2
4:1:1:1
2:2:1:0
4:1:0.5:0
[a] Entry 1 was carried out by using toluene at 80 °C, for 18 h;
entries 2–5 were carried out by using dichloromethane at room
temperature. [b] Isolated yield. [c] The relative ratio has been deter-
Figure 2. Chemical conversion of isoxazolidines 1 and 3 to 3-meth-
ylamino-2(5H)-furanones 2 and 4.
1
mined by H NMR spectroscopy of the crude reaction mixture.
In this paper, a different rearrangement route has been
highlighted that leads to the formation of β-enaminones of
type 5 valuable intermediates for the synthesis of heterocy-
cle compounds.[6] This new reaction pathway competes with
the process leading to compounds 4, according to the na-
ture of the substituents at C4 and C5 (Figure 3). We report
here the mechanistic rationalization of this new reaction
pathway together with the computational study supporting
the suggested rearrangement. DFT quantum chemical cal-
culations have allowed us to understand the factors that
ultimately control the competitive reaction routes.
major product of the cycloaddition. The stereochemical in-
formation present in the dipolarophile is completely re-
tained in the cycloadducts and the relative stereochemistry
at C4 and C5 in the formed isoxazolidine ring is predeter-
mined by the alkene geometry. The stereochemical assign-
ment has been assessed by NOE experiments (see the Sup-
porting Information). The classic pericyclic reaction of 6
with α,β-unsaturated ketones 8 and 9 proceeded with low
regio- and stereoselectivity. A better regiochemical control
towards 4-acyl-substituted isoxazolidines 11a,b and 12a,b
and increased yields were obtained by the use of the pinhole
Lewis acid as a catalyst under mild conditions (Scheme 1).[8]
Thus, in the presence of aluminum tris(2,6-diphenylphen-
oxide) (ATPH) catalyst, the crude reaction mixture shows
the formation of at least three isomers consisting of one
major product (49–62% of the total isomeric amount) be-
sides other minor products (Table 1). All the isomers were
separated and fully characterized (see the Exp. Section and
Supporting Information).
Figure 3. 3-Alkylamino-2(5H)-furanones 4 and β-enaminones 5.
Treatment of isoxazolidines 11a,b with TBAF in a 1:1
ratio led to the formation of compound 5b as the exclusive
product,[6] whereas, under the same experimental condi-
tions, both compounds 10a,b and 12a,b afford a 80:20 mix-
ture of 3-amino-2(5H)-furanones and β-enaminones (4a, 5a
from 10a,b and 4b, 5b from 12a,b; Scheme 2 and Table 2).
The structure of the obtained β-enaminones 5a,b has been
assessed on the basis of spectrometric data (see the Sup-
porting Information).
Results and Discussion
Isoxazolidines 10–12 were prepared by the reaction of
C-ethoxycarbonyl-N-methyl nitrone 6 with α,β-unsaturated
compounds 7–9. In particular, the cycloaddition of nitrone
6 with trans methyl cinnamate 7, performed in toluene at
80 °C for 18 h, proceeded in high yield (85%) to give, in
agreement with similar cycloaddition processes,[7] a mixture
of trans/cis isomers 10a and 10b (Scheme 1, Table 1).
Scheme 2. Chemical conversion of isoxazolidines 10–14 towards 3-
amino-2(5H)-furanones 4 and/or β-enaminones 5.
Scheme 1. Cycloaddition reaction of nitrone 6 with methyl cinn-
amate 7 and α,β-unsaturated ketones 8 and 9.
Treatment of isoxazolidines 10–14 with 0.2 and
No regioisomeric adducts (10c,d) were detected in the 0.5 equivalents of TBAF led to a proportional decrease of
crude reaction mixture. The diastereoisomeric ratio of 10a,b the reaction yields, thus suggesting that the base is “cap-
(4.5:1) was evaluated by the 1H NMR spectrum of the tured” by final products and that the base does not work
crude reaction mixture; C3–C5 trans isomer 10a was the as a catalyst.
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Competitive Formation of β-Enaminones and Aminofuranones
Table 2. Reaction of isoxazolidines 10–14 (I) with TBAF.
parison, the results obtained for isoxazolidines 13 and 14
are also listed.[5] To better understand which factors control
the different pathways, we investigated the two competitive
reaction channels for 13 and 11, chosen as model com-
pounds, employing quantum chemical methods (see Com-
putational Details in the Exp. Section). To study the entire
reaction course it is necessary to include explicitly the
TBAF activator and also the effects of the solvent (THF).
However, to improve the computational performance,
(nBu)4N+F– was modeled by the tetramethylammonium
fluoride (CH3)4N+F–. In the examined isoxazolidines (I),
substituents at the C4- and C5-positions are in a trans con-
figuration, whereas the substituent at C3 can assume both
a cis or a trans relationship with respect to C4. Because of
steric repulsions, (C3–C4)-trans structures, on the basis of
the present calculations, have been found to be more stable
than cis isomers (3.1 and 5.5 kcal/mol for 13-I and 11-I
compounds, respectively, see Figure S1 in the Supporting
Information). The energy of the more stable trans isomers
was taken as a reference.
I
R1
R2
4/5
[a]
10
11
12
13
14
Ph
Ph
Me
H
CO2Me
COPh
COPh
COMe
CO2Me
20:80
0:100[a]
20:80[a]
100:0[b]
100:0[b]
Me
[a] Present work. [b] See ref.[5]
Theoretical Results
The new rearrangement pathway of the isoxazolidine nu-
cleus can be rationalized as reported in Figure 4 (path B).
The carbanion II, formed by abstraction of the hydrogen
atom at C3 in I, undergoes a retroaldolization process, giv-
ing rise to compound 5 through extrusion of an aldehydic
unit. This reaction route appears to compete with the re-
arrangement, previously reported, to furanones
4
(path A)[3–5] In fact, the same reaction, performed on dif-
ferently substituted 3-ethoxycarbonyl isoxazolidines 13 and
14, afforded furanones as the exclusive products[5] (Table 2).
The competition between the two pathways leading to lac-
Several resonance structures and valence isomers (Fig-
ure 5) can be written for the carbanion II, arising from the
treatment of isoxazolidines with TBAF, thus indicating a
tones 4a and 4b and β-enaminones 5a and 5b has been ra- large negative charge delocalization that results in the weak-
tionalized on the basis of theoretical calculations. By com- ening or strengthening of some bonds. Some of these struc-
Figure 4. The rearrangement pathways of the isoxazolidine system.
Figure 5. Resonance structures, valence isomer, and hypervalent structures of carbanion II.
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D. Iannazzo, G. Lanza et al.
FULL PAPER
tures suggest the possibility of ring degradation with alde- observed.[4,5,7] This is likely due to a critical stabilization of
hyde extrusion. Actually, for a “naked” carbanion, geome- the carbanion by the (CH3)4N+ countercation (Figure 6).
try optimizations result in a barrierless expulsion of formal-
The cation polarizes the negative ion and leads to a
dehyde or benzaldehyde. Only for the carbanion from 13 build-up of extra electronic density, that is, to very small
was it possible to find a high-energy minimum that main- covalency charge. In fact, the cation reduces the negative
tains the isoxazolidine ring (see Figure S2 in the Supporting charge of the isoxazolidine ring [NBO charge on the
Information), whereas for compound 11 it was not possible (CH3)4N fragment is 0.93 e.u.] and in turn prevents sponta-
to locate a stable carbanion of this kind. This consideration neous retroaldolization. In this perspective, all the calcula-
highlights two important aspects: there is an intrinsic ten- tions for the two competitive reaction channels have been
dency of the “naked” negatively charged isoxazolidine to- performed explicitly including countercation and solvent ef-
ward fragmentation and this tendency depends on the ring fects that greatly modulate the ionic interactions.[10]
substituents.[9] In spite of this great tendency towards ring
By comparing metrical parameters of the isoxazolidine
degradation, however, the latter is seldom experimentally ring in the two analyzed contact ion pairs, a substantial
elongation of the O1–N2 and C4–C5 bond lengths emerges
and hence a bond weakening for 11-II with respect to 13-II
(Figure 6). Conversely, the O1–C5 bond length indicates a
bond strengthening in 11-II. These data still point out a
great tendency towards ring fragmentation of isoxazolidines
that carry sterically hindered substituents. Another impor-
Figure 6. Most stable conformation of the contact cation–anion
pairs (II) of the isoxazolidines 13 and 11.
Figure 7. Localization of the countercation in the structure of IIЈ
(see Figure 4).
Figure 8. Gibbs free-energy diagram [kcal/mol] for the two competitive reactions of compound 11. Data from full geometry B3LYP/6-
31+G(d,p) optimizations in THF. Only initial reagents, final products, and stable intermediates are reported.
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Competitive Formation of β-Enaminones and Aminofuranones
tant feature for both 13-II and 11-II contact ion pairs is
Beyond the thermodynamic aspects, it is also important
observed when the countercation is located in front of the to scrutinize energetic and structural evolution of interme-
N–O bond of the isoxazolidine ring (Figure 7). diate contact ion pairs II towards the formation of the two
In this case, the structure that carries a negative charge competitive III and VI intermediates. The energy profile for
on the oxygen atom is largely stabilized; the N–O bond the formation of these intermediates has been constructed
breaks and rotations around C3–C4 and C4–C5 bonds can by using the N2–C3–C4–C5 torsional angle as a “reaction
occur, leading to the subsequent intramolecular lactoniz- coordinate” (Figure 10). The energy curves are rather flat
ation. These results clearly indicate that the countercation in the early stages of the rotation with a shallow maximum
has a pivotal role in the stability of the various structures in both senses of rotation. For a rotation greater than 20°
for the isoxazolidine anion, thus modulating the two com- in both directions with respect to the equilibrium position
petitive reaction channels.
in 11-II, highly steric demanding phenyls at the C4- and C5-
Energetics for stable intermediates and final products for positions move towards the counteraction, which is sub-
the aldehyde elimination or intramolecular lactonization sequently forced to move far away. Thus, the ionic stabiliza-
are reported in Figures 8 and 9 for compounds 11 and 13, tion is reduced and the isoxazolidine ring increases its nega-
respectively. Related optimized structures are reported in tive charge resulting in a spontaneous retroaldolization with
the Supporting Information (see Figures S3 and S4 in the formation of 11-VI (∆G‡ = 1.2 kcal/mol; see Figure S5 in
Supporting Information).
the Supporting Information for the transition-state struc-
The energy curves for the two reaction channels are sim- ture).
ilar. Hydrogen abstraction by (CH3)4N+F–, leading to the
For the 13-II contact ion pair, rotations around the C3–
formation of the contact ion pair II, is highly endoergonic C4 bond result in a very different behavior because of the
for both analyzed compounds. Subsequent reaction path- absence of sterically demanding substituents at positions C4
ways are largely exoergonic and hence irreversible. The al- and C5 of the isoxazolidine ring. Upon rotations greater
dehyde elimination seems thermodynamically favored for than 20° from the equilibrium position, in both directions,
isoxazolidine 11 because of the large energy released in the (CH3)4N+ countercation undergoes large displacements
fragmentation of the sterically hindered isoxazolidine ring. and synchronously the C4–C5 bond undergoes large rota-
Conversely, the lactonization process is thermodynamically tions to approach the countercation to the O1, with the con-
favored for compound 13.
sequent opening of the heterocyclic system. The activation
Figure 9. Gibbs free-energy diagram [kcal/mol] for the two competitive reactions of 13. Data from full geometry B3LYP/6-31+G(d,p)
optimizations in THF. Only initial reagents, final products, and stable intermediates are reported.
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D. Iannazzo, G. Lanza et al.
FULL PAPER
state structure was found with an activation free energy of
3.1 kcal/mol (see Figure S5 in the Supporting Information
for the transition-state structure). After that, a profound
structural rearrangement occurs and the intermediate 13-VI
together with formaldehyde are produced.
According to these theoretical data, the retroaldolization
is thermodynamically and kinetically favored for isoxazolid-
ine 11, whereas, on the contrary, the lactonization is ther-
modynamically and kinetically favored for isoxazolidine 13.
These results are in full agreement with the experimental
evidence and can be used also to rationalize the data ob-
tained for related isoxazolidines 10, 12, and 14 (Table 2).
Thus, by starting from the less substituted isoxazolidine 13,
the replacement in the isoxazolidine ring of H with CH3 at
C5 and COMe with CO2Me at C4 (14) does not produce a
significant change in the ratio of the final products and lac-
tones are exclusively formed. Upon increasing markedly the
steric hindrance of the substituents (phenyl group at C4 or
C5 centers as in 10 and 12), the alternative route becomes
competitive and only 20% of the lactone is formed.
When steric hindrance in both C4 and C5 centers further
increases (compound 11), the thermodynamic drive toward
aldehyde extrusion is maximized and countercation mo-
bility is minimized and hence the β-enaminone is exclusively
formed.
Figure 10. Electronic energy profile for rotation around C3–C4 in
the 11-II and 13-II contact ion pairs. Data from full geometry
B3LYP/6-31+G(d,p) optimizations in THF. Selected geometries
showing important structural evolutions. The energy and N2–C3–
C4–C5 torsional bond angle of contact ion pairs 13-II and 11-II
have been assumed as references.
Conclusions
free energy for this process is 2.7 kcal/mol (see Figure S6 in
the Supporting Information for a transition-state structure).
As the C3–C4 bond is rotated by 180Ϯ20°, the nucleo-
philic –O1– group approaches the carboxyethyl and lactoni-
zation occurs.
We have also quantified the energy barrier for the com-
petitive aldehyde extrusion in the 13-II contact ion pair. The
energy profile has been constructed by using the O1–N2
bond length as the “reaction coordinate” (Figure 11). The
energy increases quickly upon the O1–N2 bond lengthening
and reaches the maximum at 1.73 Å, for which a transition-
A new reaction pathway of 3-alkoxycarbonyl-4-acyl- or
3,4-dialkoxycarbonyl-substituted isoxazolidines 10–12 to β-
enaminones 5, by treatment with TBAF is reported. This
reaction channel competes with the route leading to 3-
methylamino-2(5H)-furanones 4, according to the nature of
the substituents at C4 and C5 The mechanistic rationaliza-
.
tion of this new pathway has been performed according to
a computational study, which has allowed us to understand
the factors that ultimately control the competitive reaction
routes.
All the relevant elementary steps of the two alternative
mechanisms (lactonization and retroaldolization) for two
representative isoxazolidines 11 and 13 have been analyzed
by quantum chemical methods. Any realistic theoretical
modeling requires the explicit inclusion of countercation
and solvent effects. Isoxazolidine ring activation by TBAF
leads to the formation of stable 11-II and 13-II contact ion
pairs that are the starting point of both reaction channels.
The oxygen atoms of carboxyl groups at the C3 and C4
positions chelate the countercation and successive dynamics
determine the final pathways. The retroaldolization occurs
preferentially because of the steric strain posed by the
largely hindered ring substituents in 11-II, which prevents
the possibility of the countercation passing from one side
to the other side of the isoxazolidine ring to stabilize the
alkoxy anion IIЈ (Figure 4). Conversely, the reduced size of
the ring substituents for 13-II decreases the repulsive inter-
actions and, hence, the intrinsic tendency toward ring frag-
mentation. Furthermore, the mobility of countercation is
Figure 11. Electronic energy profile for aldehyde extrusion from the
13-II contact ion pair along the O1–N2 reaction coordinate. Data
from full geometry B3LYP/6-31+G(d,p) optimizations in THF. Se-
lected geometries showing important structural evolutions are re-
ported.
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Competitive Formation of β-Enaminones and Aminofuranones
highly permitted and can assist rotation around C3–C4 and
C4–C5 for the competitive lactonization.
In general, the relative importance of the two reaction
channels may be predicted by considering the electronic and
steric features of substituents on the isoxazolidine ring.
74.2, 81.3, 126.8, 128.4, 128.6, 138.3, 169.6, 171.7 ppm. HRMS
(EI): calcd. for C15H19NO5 [M]+ 293.1263; found 293.1265.
C15H19NO5 (293.32): calcd. C 61.42, H 6.53, N 4.78; found C
61.38, H 6.49, N 4.72.
3-Ethyl 4-Methyl (3SR,4RS,5RS)-2-Methyl-5-phenylisoxazolidine-
3,4-dicarboxylate (10b): Rf = 0.48. Colorless oil (0.343 g, 15.4%).
1H NMR (CDCl3, 500 MHz): δ = 1.30 (t, J = 7.0 Hz, 3 H, CH3),
2.91 (s, 3 H, N-CH3), 3.66 (dd, J = 3.5, 7.0 Hz, 1 H, 4-H), 3.71 (s,
3 H, OCH3), 3.77 (d, J = 3.5 Hz, 1 H, 3-H), 4.21 (q, J = 7.0 Hz, 2
H, O-CH2), 5.34 (d, J = 7.0 Hz, 1 H, 5-H), 7.28–7.47 (m, 5 H, Ar)
ppm. 13C NMR (CDCl3, 125 MHz): δ = 14.1, 52.3, 56.5, 58.2, 62.1,
74.2, 81.5, 126.9, 127.7, 128.6, 139.5, 168.3, 170.3 ppm. HRMS
(EI): calcd. for C15H19NO5 [M]+ 293.1263; found 293.1259.
C15H19NO5 (293.32): calcd. C 61.42, H 6.53, N 4.78; found C
61.37, H 6.45, N 4.81.
Experimental Section
Computational Details: Computations were performed at the den-
sity functional level employing the hybrid B3LYP functional with
the 6-31+G** basis set. The geometries were optimized by using
standard gradient techniques within the restricted Hartree–Fock
formalism and including explicitly solvent effects. The “distin-
guished reaction coordinate” procedure has been used to analyze
the full progress of the lactonization and retroaldolization occur-
ring in intermediates 11-II and 13-II. The geometry optimization
of the first point was begun from the ground-state structure of 11-
II and 13-II contact ion pairs. As the reaction proceeds, the starting
structure in each geometry optimization was taken from the imme-
diately preceding point. Once the approximate transition-state
structure was determined, the true transition state was refined by
using the second derivatives of the energy techniques. All stationary
points presently characterized by vibrational analysis are true min-
ima or true transition states (no imaginary frequency and only one
imaginary frequency, respectively).
General Procedure for the Synthesis of Isoxazolidines 11a,d and 12a–
c: Trimethylaluminum (0.2 mL, 2  solution in toluene) was added
to a solution of 2,6-diphenylphenol (290 mg, 0.38 mmol) in dry
dichloromethane (20 mL) at 0 °C under a N2 atmosphere and the
solution was left stirring for 30 min at this temperature. Then, al-
kene 8 or 9 (3.8 mmol) was added at 0 °C and, after 30 min, a
solution of nitrone 6 (3.8 mmol in 10 mL of CH2Cl2) was added
dropwise over 20 min. The reaction mixture was stirred for 18 h at
room temperature. Then, the mixture was filtered through a Celite
pad, the filtrate was evaporated in vacuo, and the residue subjected
to medium pressure liquid chromatography (MPLC) by using cy-
clohexane/ethyl acetate (9:1) as the eluent. The reaction of nitrone
6 and (E)-chalcone 8 affords a mixture of stereoisomers 11a–d
(yield 86%), whereas the reaction of nitrone 6 and (E)-1-phenylbut-
2-en-1-one (9) affords a mixture of stereoisomers 12a–c (yield
85%).
The computed energies were corrected for zero-point vibrational
and thermal energies and entropies to obtain free-energy changes
(∆G°298) at 298 K. Solvent effects were modeled by using the polar-
ized continuum method (PCM) adopting a 7.64 dielectric constant
for THF solvent as implemented in the G09 program.[11]
Methods: Solvents and reagents were used as received from com-
mercial sources. Melting points were determined with a Kofler ap-
paratus and are reported uncorrected. Elemental analyses were per-
formed with a Perkin–Elmer elemental analyzer. NMR spectra (1H
NMR recorded at 500 MHz, 13C NMR recorded at 125 MHz) were
obtained on Varian Instruments and are referenced in ppm relative
to TMS or the solvent signal. Mass spectroscopy data were col-
lected on an HRMS-EI. Thin-layer chromatographic separations
were performed on Merck silica gel 60-F254 precoated aluminum
plates. Flash chromatography was accomplished on Merck silica
gel (200–400 mesh). Preparative separations were carried out by a
MPLC Büchi C-601 by using Merck silica gel 0.040–0.063 mm and
the eluting solvents were delivered by a pump at the flow rate of
3.5–7.0 mLmin–1. The identification of samples from different ex-
periments was secured by mixed melting points and superimposable
NMR spectra. (E)- and (Z)-C-(ethoxycarbonyl)-N-methyl-nitrones
6 were prepared according to described procedures.[12]
Ethyl (3SR,4SR,5SR)-5-Benzoyl-2-methyl-4-phenylisoxazolidine-3-
carboxylate (11c): Rf = 0.50. Colorless oil (0.159 g, 12.4%). 1H
NMR (CDCl3, 500 MHz): δ = 0.85 (t, J = 7.0 Hz, 3 H, CH3), 2.92
(s, 3 H, NCH3), 3.75 (d, J = 8.6 Hz, 1 H, 3-H), 3.79 (q, J = 7.0 Hz,
2 H, OCH2), 4.43 (dd, J = 5.5, 8.6 Hz, 1 H, 4-H), 5.44 (d, J =
5.5 Hz, 1 H, 5-H), 7.31–7.94 (m, 10 H, Ar) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 13.6, 45.0, 54.1, 60.8, 74.6, 85.7, 127.7,
128.5, 128.6, 129.0, 129.4, 133.8, 138.1, 134.6, 167.9, 194,5 ppm.
HRMS (EI): calcd. for C20H21NO4 [M]+ 339.1471; found 339.1476.
C20H21NO4 (339.39): calcd. C 70.78, H 6.24, N 4.13; found C
70.75, H 6.21, N 4.16.
Ethyl (3SR,4RS,5RS)-5-Benzoyl-2-methyl-4-phenylisoxazolidine-3-
carboxylate (11d): Rf = 0.45. Colorless oil (0.158 g, 12.3%). 1H
NMR (CDCl3, 500 MHz): δ = 1.23 (t, J = 7.5 Hz, 3 H, CH3), 2.92
(s, 3 H, NCH3), 3.45 (d, J = 8.0 Hz, 1 H, 3-H), 4.17 (q, J = 7.5 Hz,
2 H, OCH2), 4.69 (dd, J = 5.0, 8.0 Hz, 1 H, 4-H), 5.17 (d, J =
5.0 Hz, 1 H, 5-H), 7.28–7.97 (m, 10 H, Ar) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 13.6, 44.7, 54.2, 61.5, 74.3, 85.9, 127.6,
128.0, 128.3, 129.0, 129.4, 133.2, 134.8, 144.7, 168.6, 196.2 ppm.
HRMS (EI): calcd. for C20H21NO4 [M]+ 339.1471; found 339.1474.
C20H21NO4 (339.39): calcd. C 70.78, H 6.24, N 4.13; found C
70.79, H 6.25, N 4.10.
General Procedure for the Synthesis of Isoxazolidines 10a,b: A solu-
tion of nitrone 6 (1 g, 7.6 mmol) and methyl trans-cinnamate 7
(1.84 g, 11.4 mmol) in dry toluene (20 mL) was heated at 80 °C for
18 h. The mixture was evaporated and the resulting residue was
purified by MPLC on a silica gel with cyclohexane/ethyl acetate
(80:20) to afford a mixture of regioisomers 10a and 10b in a 4.5:1
ratio.
Ethyl (3SR,4RS,5RS)-4-Benzoyl-2-methyl-5-phenylisoxazolidine-3-
carboxylate (11b): Rf = 0.40. Colorless oil (0.158 g, 12.3%). 1H
NMR (CDCl3, 500 MHz): δ = 1.27 (t, J = 7.0 Hz, 3 H, CH3), 3.00
(s, 3 H, NCH3), 4.15 (d, J = 5.5 Hz, 1 H, 3-H), 4.27 (q, J = 7.0 Hz,
3-Ethyl 4-Methyl (3SR,4SR,5SR)-2-Methyl-5-phenylisoxazolidine-
3,4-dicarboxylate (10a): Rf = 0.52. Colorless oil (1.55 g, 69.6%). 1H
NMR (CDCl3, 500 MHz): δ = 1.29 (t, J = 8.0 Hz, 3 H, CH3), 2.94 2 H, OCH2), 4.85 (dd, J = 5.0, 7.5 Hz, 1 H, 4-H), 5.42 (d, J =
(s, 3 H, N-CH3), 3.82 (s, 3 H, OCH3), 3.89 (dd, J = 5.0 and 7.0 Hz, 7.5 Hz, 1 H, 5-H), 7.31–7.74 (m, 10 H, Ar) ppm. 13C NMR
1 H, 4-H), 4.03 (d, J = 5.0 Hz, 1 H, 3-H), 4.28 (q, J = 8.0 Hz, 2
H, O-CH2), 5.39 (d, J = 7.0 Hz, 1 H, 5-H), 7.24–7.48 (m, 5 H, Ar) 128.3, 128.6, 128.7, 133.8, 136.0, 137.8, 170.5, 197.3 ppm. HRMS
ppm. 13C NMR (125 MHz, CDCl3): δ = 14.1, 52.6, 56.1, 59.2, 61.8, (EI): calcd. for C20H21NO4 [M]+ 339.1471; found 339.1474.
(CDCl3, 125 MHz): δ = 14.1, 46.7, 61.9, 62.1, 82.8, 127.3, 128.0,
Eur. J. Org. Chem. 2010, 5897–5905
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5903

D. Iannazzo, G. Lanza et al.
FULL PAPER
C20H21NO4 (339.39): calcd. C 70.78, H 6.24, N 4.13; found C
70.74, H 6.20, N 4.16.
1-Ethyl 4-Methyl 2-(Methylamino)fumarate (5a): Light-yellow oil
(0.135 g, 72%) from 10a or 10b (293 mg). 1H NMR (CDCl3,
500 MHz): δ = 1.33 (t, J = 7.2 Hz, 3 H, CH3), 3.02 (d, J = 5.2 Hz,
3 H, NCH3), 3.69 (s, 3 H, OCH3), 4.34 (q, J = 7.2 Hz, 2 H, OCH2),
5.22 (s, 1 H, CH=), 7.99 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3,
125 MHz): δ = 21.4, 26.8, 45.2, 75.9, 117.9, 142.5, 167.0, 193.1
ppm. HRMS (EI): calcd. for C8H13NO4 [M]+ 187.0845; found
187.0842. C8H13NO4 (187.20): calcd. C 51.33, H 7.00, N 5.48;
found C 51.30, H 7.04, N 5.46.
Ethyl (3SR,4SR,5SR)-4-Benzoyl-2-methyl-5-phenylisoxazolidine-3-
carboxylate (11a): Rf = 0.21. Colorless oil (0.632 g, 49%). 1H NMR
(CDCl3, 500 MHz): δ = (t, J = 7.2 Hz, 3 H, CH3), 2.90 (s, 3 H,
NCH3), 3.75 (d, J = 9.3 Hz, 1 H, 3-H), 3.92 (q, J = 7.2 Hz, 2 H,
OCH2), 4.51 (dd, J = 7.7, 9.3 Hz, 1 H, 4-H), 5.25 (d, J = 7.7 Hz,
1 H, 5-H), 7.22–7.64 (m, 10 H, Ar) ppm. 13C NMR (CDCl3,
125 MHz): δ = 13.7, 45.0, 60.6, 61.2, 73.0, 82.5, 126.9, 127.6, 128.4,
128.5, 128.6, 129.9, 133.4, 136.4, 168.2, 196.2 ppm. HRMS (EI):
4-Benzoyl-5-methyl-3-(methylamino)furan-2(5H)-one (4b): Colorless
calcd for C20H21NO4 [M]+ 339.1471; found 339.1469. C20H21NO4 oil (42 mg, 18%) from 12a or 12b (277 mg). 1H NMR (CDCl3,
(339.39): calcd. C 70.78, H 6.24, N 4.13; found C 70.73, H 6.26, N
4.10.
500 MHz): δ = 1.40 (d, J = 4.5 Hz, 3 H, CH3), 3.20 (d, J = 3.5 Hz,
3 H, NCH3), 5.05 (q, J = 4.5 Hz, 1 H, 5-H), 6.70 (br. s, NH), 7.40–
7.90 (m, 5 H, Ar) ppm. 13C NMR (CDCl3, 125 MHz): δ = 18.2,
31.2, 51.9, 75.0, 110.6, 146.7, 162.6, 170.6 ppm. HRMS (EI): calcd.
for C13H13NO3 [M]+ 231.0895; found 231.0893. C13H13NO3
(231.25): calcd. C 67.52, H 5.67, N 6.02; found C 67.50, H 5.66, N
6.00.
Ethyl (3SR,4SR,5SR)-5-Benzoyl-2,4-dimethylisoxazolidine-3-carb-
oxylate (12c): Rf = 0.45. Light-yellow oil (0.081 g, 7.7%). 1H NMR
(CDCl3, 500 MHz): δ = 1.35 (t, J = 7.0 Hz, 3 H, CH3), 1.42 (d, J
= 7.5 Hz, 3 H, CH3), 2.90 (s, 3 H, NCH3), 3.08 (d, J = 8.5 Hz, 1
H, 3-H), 3.52 (ddq, J = 5.5, 7.5, 8.5 Hz, 1 H, 4-H), 4.27 (q, J =
7.0 Hz, 2 H, OCH2), 4.75 (d, J = 5.5 Hz, 1 H, 5-H), 7.44–8.15 (m,
5 H, Ar) ppm. 13C NMR (CDCl3, 125 MHz): δ = 11.2, 14.2, 44.3,
44.8, 61.0, 73.3, 82.1, 128.2, 128.8, 133.6, 138.0, 169.2, 197.2 ppm.
HRMS (EI): calcd. for C15H19NO4 [M]+ 277.1314; found 277.1319.
C15H19NO4 (277.32): calcd. C 64.97, H 6.91, N 5.05; found C
64.99, H 6.88, N 5.09.
(Z)-Ethyl 2-(Methylamino)-4-oxo-4-phenylbut-2-enoate (5b): Yellow
oil (200 mg, 90%) from 11a or 11b (339 mg); (167 mg, 72%) from
1
12a or 12b (277 mg). H NMR (CDCl3, 500 MHz): δ = 1.35 (t, J
= 7.3 Hz, 3 H, CH3), 3. 12 (d, J = 5.5 Hz, 3 H, NCH3), 4.36 (q, J
= 7.3 Hz, 2 H, OCH2), 6.01 (s, 1 H, CH=), 7.5–8.1 (m, 5 H, Ar),
10.75 (br. s, 1 H, NH) ppm. 13C NMR (CDCl3, 125 MHz): δ =
14.8, 32.4, 62.8, 92.3, 127.2, 128.2, 131.8, 140.3, 154.8, 164.0, 191.5
ppm. HRMS (EI): calcd. for C13H15NO3 [M]+ 233.1052; found
233.1058. C13H15NO3 (233.27): calcd. C 66.94, H 6.48, N 6.00;
found C 66.91, H 6.45, N 6.05.
Ethyl (3SR,4RS,5SR)-4-Benzoyl-2,5-dimethylisoxazolidine-3-carb-
oxylate (12b): Rf = 0.40. Light-yellow oil (0.161 g, 15.3%). 1H
NMR (CDCl3, 500 MHz): δ = 0.99 (d, J = 6.5 Hz, 3 H, CH3), 1.22
(t, J = 7.0 Hz, 3 H, CH3), 2.94 (s, 3 H, NCH3), 4.05 (d, J = 6.5 Hz,
1 H, 3-H), 4.19 (q, J = 7.0 Hz, 2 H, OCH2), 4.59 (dq, J = 6.5,
8.5 Hz, 1 H, 5-H), 4.75 (dd, J = 6.5, 8.5 Hz, 1 H, 4-H), 7.26–7.96
(m, 5 H, Ar) ppm. 13C NMR (CDCl3, 125 MHz): δ = 14.3, 17.7,
46.4, 57.0, 62.4, 72.1, 74.7, 128.8, 128.9, 133.5, 138.9, 169.7, 196.8
ppm. HRMS (EI): calcd. for C15H19NO4 [M]+ 277.1314; found
277.1316. C15H19NO4 (277.32): calcd. C 64.97, H 6.91, N 5.05;
found C 64.95, H 6.89, N 5.02.
Supporting Information (see also the footnote on the first page of
this article): Additional figures, NMR characterization of com-
pounds 10–12, computed structures for high lying minima and
transition states, Cartesian coordinates and NMR spectra of com-
pounds 4, 5, 10–12.
Acknowledgments
Ethyl (3SR,4SR,5RS)-4-Benzoyl-2,5-dimethylisoxazolidine-3-carb-
oxylate (12a): Rf = 0.38. Light-yellow oil (0.053 g, 62%). 1H NMR
(CDCl3, 500 MHz): δ = 0.98 (t, J = 6.0 Hz, 3 H, CH3), 1.43 (d, J
= 6.0 Hz, 3 H, CH3), 2.86 (s, 3 H, NCH3), 3.61 (d, J = 9.5 Hz, 1
H, 3-H), 3.97 (q, J = 6.0 Hz, 2 H, OCH2), 4.18 (dd, J = 7.5, 9.5 Hz,
1 H, 4-H), 4.40 (dq, J = 6.0, 7.5 Hz, 1 H, 5-H), 7.44–7.92 (m, 5 H,
Ar) ppm. 13C NMR (CDCl3, 125 MHz): δ = 14.0, 17.8, 46.3, 57.3,
62.0, 71.5, 76.0, 128.4, 128.9, 137.8, 139.0, 169.4, 196.9 ppm.
HRMS (EI): calcd. for C15H19NO4 [M]+ 277.1314; found 277.1317.
C15H19NO4 (277.32): calcd. C 64.97, H 6.91, N 5.05; found C
64.94, H 6.88, N 5.03.
We gratefully acknowledge the Ministero dell’Università e della
Ricerca (MIUR) (Progetto Nazionale 2008–2010: Amminoacidi
conformazionalmente rigidi: versatili building blocks per la sintesi
regio- e stereoselettiva di nuovi sistemi policiclici catalizzata da me-
talli di transizione; Progettazione e sintesi stereoselettiva di com-
posti eterociclici quali nuovi agenti antivirali) and the University
of Catania and Messina for their generous support of this work.
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4a,b and β-Enaminones 5a,b: TBAF (1.1 mL, 1.1 mmol, 1  in
THF) was added to a solution of isoxazolidine 10–12 (1 mmol) in
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Methyl 4-(Methylamino)-5-oxo-2-phenyl-2,5-dihydrofuran-3-carb-
oxylate (4a): Colorless oil (0.034 g, 18%) from 10a or 10b (293 mg).
1H NMR (CDCl3, 500 MHz): δ = 3.36 (d, J = 5.5 Hz, 3 H, NCH3),
3.61 (s, 3 H, OCH3), 5.95 (s, 1 H, 5-H), 6.54 (br. s, 1 H, NH) 7.27–
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C13H13NO4 (247.25): calcd. C 63.15, H 5.30, N 5.67; found C
63.12, H 5.32, N 5.65.
5904
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Eur. J. Org. Chem. 2010, 5897–5905

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Received: April 26, 2010
Published Online: September 10, 2010
Eur. J. Org. Chem. 2010, 5897–5905
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5905