4-Isoxazolines and pyrroles from allenoates

Article abstract of DOI:10.1016/j.tet.2010.06.010

The synthesis of 4-isoxazolines via 1,3-dipolar cycloaddition of nitrones generated from allenoates and the subsequent thermal rearrangement to pyrroles is reported. The selection of the reaction conditions allowed the isolation of the initial 1,3-dipolar

Full text of DOI:10.1016/j.tet.2010.06.010

Tetrahedron 66 (2010) 6078e6084
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4-Isoxazolines and pyrroles from allenoates
*
Susana M.M. Lopes, Cláudio M. Nunes, Teresa M.V.D. Pinho e Melo
Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 4-isoxazolines via 1,3-dipolar cycloaddition of nitrones generated from allenoates and
the subsequent thermal rearrangement to pyrroles is reported. The selection of the reaction conditions
allowed the isolation of the initial 1,3-dipolar cycloadducts, the 4-isoxazolines, or the pyrrole derivatives.
The isomerization of the parent system (4-isoxazoline) was examined by carrying out quantum chemical
calculations and corroborated the favourability of the 4-isoxazoline rearrangement to five-membered
heterocycles via 2-acylaziridine intermediates.
Received 12 February 2010
Received in revised form 28 May 2010
Accepted 2 June 2010
Available online 10 June 2010
Keywords:
4-Isoxazolines
Ó 2010 Elsevier Ltd. All rights reserved.
Pyrroles
Allenes
Nitrones
1,3-Dipolar cycloaddition
Thermal rearrangements
Microwave-assisted synthesis
1. Introduction
We have been interested in the use of allenes as starting ma-
terials for the preparation of acyclic and cyclic derivatives.12 In this
Allenes are particularly interesting molecules due to the in-
herent instability associated to the cumulated double bonds, which
has been explored for various synthetic purposes.1e5 Despite vari-
ous known contributions to the chemistry of these building blocks,
their use in 1,3-dipolar cycloadditions either as dipolarophiles or
1,3-dipole precursors is a less explored research area.5 Neverthe-
less, allenes have been used to generate cyclic and acyclic nitrones
through the reaction with hydroxylamines.6 On the other hand, the
main strategy to obtain 4-isoxazolines (2,3-dihydroisoxazoles) has
been the 1,3-dipolar cycloaddition between nitrones and alkynes or
allenes.7e9 These heterocycles are also particularly interesting
synthons for cyclic and acyclic compounds due to their readiness to
undergo rearrangement reactions; the driving force being the rel-
atively low thermochemical stability of the NeO bond. The most
general reactivity pattern of 4-isoxazolines is the thermal isomer-
ization to 2-acylaziridines. The azomethine ylides generated via
conrotatory aziridine ring opening can undergo a proton shift fol-
lowed by cyclization leading to pyrroles.7,8,10 The development of
synthetic routes to pyrroles is also a relevant research goal since
these compounds represent an important class of heterocycles due
to their broad distribution in nature as constituents of the frame-
work of a range of natural products and also of synthetic bioactive
molecules.11
context, we decided to further explore the synthesis of 4-isoxazo-
lines via 1,3-dipolar cycloaddition of nitrones generated from
allenoates and the subsequent thermal rearrangement to pyrrole
derivatives (Scheme 1).
R1
•
CO2Bn
R2NHOH
R2
N
R1
O
R1
R3
R4
CO2Bn
R3
R4
Scheme 1.
R3
R4
BnO2C
R1
R2
N
R2
N
BnO2C
O
2. Results and discussion
Buta-2,3-dienoates 113 were efficiently converted into the cor-
responding nitrones 2 upon reaction with N-methylhydroxylamine
hydrochloride at room temperature in the presence of triethyl-
amine (Scheme 2). The isolation of the nitrones did not required
further purification other than washing the organic phase with
water followed by evaporation of the dichloromethane. Triethyl-
amine can be replaced by sodium hidrogenocarbonate making the
isolation of the nitrones even easier, only filtration of the reaction
mixture followed by evaporation of the organic solvent is required.
* Corresponding author. Tel.: þ351 239 854475; e-mail address: tmelo@ci.uc.pt
(T.M.V.D. Pinho e Melo).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.010

S.M.M. Lopes et al. / Tetrahedron 66 (2010) 6078e6084
6079
Table 2
R
1H and 13C NMR data for 2,3-dihydro-1H-pyrrole 4a
R
MeNHOH.HCl / NEt3
DCM, rt
O
CO2Bn
•
7
N
Me
CO2Bn
Me
8
6
9
N
5
2
Me
CO2Me
1
1a R = H
1b R = Me
1c R = Ph
2a R = H
86%
3
2b R = Me 88%
2c R = Ph 89%
OH
4
PhH2CO2C
13 12
CO2Me
10 11
4
Scheme 2.
C
1H (ppm)
13C (ppm)
C-6
C-7
C-9
C-11
C-2
2.36 (s, 3H)
2.93 (s, 3H)
3.65 (s, 3H)
3.78 (s, 3H)
4.43 (s, 1H)
12.6
32.5
52.4
53.4
74.3
64.8
The reactivity of nitrone 2a, generated from allene 1a, towards
dimethyl acetylenedicarboxylate (DMAD) was explored (Table 1).
Carrying out the reaction at room temperature for 15 min the cor-
responding 1,3-dipolar cycloadduct 3 was isolated as single product
in 66% overall yield (entry 1). The same 4-isoxazoline was obtained
in slightly lower yield performing the reaction at 50 ꢀC for 1 h
(entry 2). Interestingly, the condensation of nitrone 2a with DMAD
at 120 ꢀC afforded 3-hydroxy-2,3-dihydro-1H-pyrrole 4 as the only
product (entry 3).
C-13
5.00 (d, 1H, J¼12.4 Hz)
5.21 (d, 1H, J¼12.4 Hz)
C-3
C-4
C-5
d
d
d
81.1
100.5
164.4
a
Chemical shifts of the phenyl group and the carbonyl carbons are not included.
2,3-Dihydro-1H-pyrrole 4 could also be prepared in 56% yield by
heating at 120 ꢀC a solution of 4-isoxazoline 3 in toluene for 8 h. On
the other hand, compound 4 undergoes dehydration in refluxing
toluene to give pyrrole 5 in 69% yield. These results allowed to
conclude that 2,3-dihydro-1H-pyrrole 4 results from the thermal
rearrangement of 4-isoxazoline 3 and is an intermediate of the
4-isoxazoline-pyrrole rearrangement.
The work was extended to the reaction of allenes 1b and 1c with
N-methylhydroxylamine to generate the corresponding nitrones
followed by cycloaddition with DMAD (Table 3). Carrying out the
cycloaddition of nitrone 2b at room temperature for 30 min
4-isoxazoline 6a was isolated in 42% overall yield (entry 1). A slight
decrease in yield was observed when the reaction was performed at
room temperature with a longer reaction time (entry 2). The re-
action of nitrone 2b with DMAD at 120 ꢀC for 20 h gave pyrrole 7a
in modest yield (entry 3). More efficient process was achieved
under microwave irradiation. Isoxazoline 6a could be obtained in
56% overall yield via microwave-induced cycloaddition at 60 ꢀC for
just 1 min (entry 4). On the other hand, pyrrole 7a was isolated as
single product in 35% yield carrying out the microwave irradiation
at 200 ꢀC for 15 min (entry 5). In this case, no evidence of the for-
mation of the 3-hydroxy-2,3-dihydro-1H-pyrrole that would result
from the thermal rearrangement of 4-isoxazoline 6a was observed.
Me
BnO2C
N
1. MeNHOH.HCl / Base
DCM, rt, 1.5 h
BnO2C
O
Me
•
2. DMAD, Toluene
MeO2C
CO2Me
1a
3
Me
Me
N
N
Me
CO2Me
CO2Me
Me
BnO2C
CO2Me
OH
CO2Me
BnO2C
4
5
Table 1
Reaction of nitrone 2a with DMAD
Entry
Reaction conditions (Second step)
Products (overall yield %)
1
2
3
4
5
6
7
8
9
Rt, 15 min
3 (66%)
3 (59%)
4 (45%)
3 (57%)
50 ꢀC, 1 h
120 ꢀC, 3 h
MW, 40 ꢀC, 1 min
MW, 50 ꢀC, 1 min
MW, 60 ꢀC, 1 min
MW, 150 ꢀC, 1 h
MW, 200 ꢀC, 15 mina
MW, 250 ꢀC, 5 mina
3 (60%)
3 (78%)þ4 (3%)
4 (25%)þ5 (32%)
5 (46%)
5 (43%)
a
Table 3
Carried out in trichlorobenzene.
Reaction of nitrones 2b and 2c with DMAD
BnO2C
Me
N
Me
N
R
R
1H NMR and 13C NMR data of compound 4, are collected in
Table 2. The assignment was supported by a two-dimensional
HMQC spectrum (400 MHz). The assignment of the hydroxylic
proton of alcohol 4 in the 1H NMR spectrum was confirmed by
a D2O exchange experiment.
CO2Me
CO2Me
1. MeNHOH.HCl
Base
O
R
•
DCM, rt, 1.5 h
2. DMAD, Toluene
MeO2C
CO2Me
BnO2C
BnO2C
1b R = Me
1c R = Ph
6a R = Me
6b R = Ph
7a R = Me
7b R = Ph
The reaction of nitrone 2a with DMAD under microwave irra-
diation was also explored (Table 1). Carrying out the microwave-
assisted reaction at 40 ꢀC for just 1 min afforded 4-isoxazoline 3 in
57% yield, whereas, at 50 ꢀC the same heterocycle was obtained in
60% yield (Entries 4 and 5). The irradiation at 60 ꢀC for 1 min led to
4-isoxazoline 3 as the major product (78%) together with the for-
mation of 2,3-dihydro-1H-pyrrole 4 in 3% yield (entry 6). At higher
temperature and longer reaction time (150 ꢀC, 1 h) the products
were 2,3-dihydro-1H-pyrrole 4 (25%) and 1H-pyrrole 5 (32%) (entry
7). The irradiation at higher temperature (200e250 ꢀC, 5e15 min)
using trichlorobenzene as solvent allowed the synthesis of
1H-pyrrole 5 as the only product (Entries 8 and 9).
Entry Allene Reaction conditions (Second step) Product (overall yield %)
1
2
3
4
5
6
7
8
9
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
rt, 30 min
rt, 2 h
120 ꢀC, 20 h
MW, 60 ꢀC, 1 min
MW, 200 ꢀC, 15 mina
rt, 1 h
6a (42%)
6a (38%)
7a (18%)
6a (56%)
7a (35%)
6b (55%)
6b (28%)
7b (37%)
6b (52%)
7b (39%)
rt, 4 h
120 ꢀC, 24 h
MW, 60 ꢀC, 1 min
MW, 200 ꢀC, 15 mina
10
a
Carried out in trichlorobenzene.

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S.M.M. Lopes et al. / Tetrahedron 66 (2010) 6078e6084
The reaction of nitrone 2c with DMAD carried out at room tem-
perature for 1 h afforded 4-isoxazoline 6b in 55% overall yield
(entry 6), whereas, with a longer reaction time the same product
was obtained in lower yield (entry 7). Under conventional ther-
molysis the cycloaddition led to pyrrole 7b in 37% yield (entry 8).
The microwave-induced reaction allowed the selective synthesis of
4-isoxazoline 6b or pyrrole 7b depending on the reaction condi-
tions (Entries 9 and 10).
Me
N
Me
N
BnO2C
Me
EtO2C
Toluene
Me
CO2Et
Ph
O
120 ºC, 4 d
54%
BnO2C
Ph
8a
9a
Scheme 3.
The behaviour of nitrones 2 towards ethyl phenylpropiolate was
then studied (Table 4). The room temperature cycloaddition of
nitrone 2a led to 4-isoxazoline 8a in a regioselective fashion (En-
tries 1 and 2). Carrying the reaction at 50 ꢀC for 17 h, the same
product was obtained in 54% yield (entry 3). However, at higher
temperature (120 ꢀC) pyrrole 9a was obtained as single product in
good overall yield (Entries 4 and 5). Microwave-assisted cycload-
dition for a period of 10 min at 60 ꢀC, followed by irradiation at
120 ꢀC for 3 min allowed the synthesis of 4-isoxazoline 8a in 79%
yield (entry 7). Under microwave irradiation at 120 ꢀC for 4 min the
reaction of nitrone 2a with ethyl phenylpropiolate gave 4-iso-
xazoline 8a in lower yield (entry 8). Pyrrole 9a could be obtained
selectively in 62% overall yield carrying out the microwave-induced
reaction at 200 ꢀC for 15 min (entry 9). The structural assignment of
pyrrole 9a was confirmed by a NOESY experiment. In fact, in the
NOESY spectrum no connectivity was observed between the
methyl protons at N-1 and the phenyl protons at C-3.
10). The thermolysis at 120 ꢀC for 5 d afforded 4-isoxazoline 8b and
pyrrole 9b in 25% and 13% yield, respectively (entry 11). Selecting
the appropriated reaction conditions the microwave-induced cy-
cloaddition of 2b with ethyl phenylpropiolate allowed the selective
synthesis of either 4-isoxazoline 8b or pyrrole 9b (Entries 12e14).
The reactivity of nitrone 2c in the presence of ethyl phenyl-
propiolate was also studied. 4-Isoxazoline 8c could be obtained in
moderate yield carrying out the reaction under conventional
heating or under microwave irradiation (Entries 15 and 16). The
microwave-assisted reaction of nitrone 2c performed at 200 ꢀC for
15 min afforded to pyrrole 9c in 26% yield (entry 17).
The reaction of nitrone 2a, generated from allenoate 1a, with
methyl propiolate was explored (Table 5). Interestingly, the room
temperature cycloaddition led to pyrrole 11b as single
regioisomer (Entries 1 and 2), whereas, at 120 ꢀC pyrrole 11a was
the major product or even the only product. In fact, with a re-
action time of 2.5 h 11a was isolated in 58% yield together with
the pyrrole 11b in 9% yield (entry 4) and with a longer reaction
time only pyrrole 11a was formed in 58% yield (entry 5). Carrying
out the cycloaddition at 50 ꢀC for 2 h a mixture of isoxazolines 10
was obtained (entry 3). These isoxazolines showed low stability
on standing at room temperature. These results indicate that the
1,3-dipolar cycloaddition of nitrone 2a with methyl propiolate
leads to a mixture of regioisomeric 4-isoxazolines. However, due
to the lack of stability of the cycloadducts and with the appro-
priate reaction conditions pyrrole 11a or 11b can be isolated as
single products. Another conclusion can be drawn, 4-isoxazoline
10b is less stable than 10a, since higher temperature favours the
synthesis of pyrrole 11a (Entries 4 and 5). In line with this ob-
servation, from the microwave-assisted cycloaddition only pyr-
role 11a could be isolated. In fact, although microwave irradiation
at 50 ꢀC for 2 min gave isoxazolines 10 (entry 6) at 60 ꢀC with
1 min irradiation time, isoxazolines were formed together with
pyrrole 11a (entry 7) and at higher temperature only pyrrole 11a
was isolated (entry 8 and 9).
Table 4
Reaction of nitrones 2a, 2b and 2c with ethyl phenylpropiolate
BnO2C
Me
N
Me
N
R
R
CO2Et
Ph
O
R
•
1. MeNHOH.HCl
Base
EtO2C
Ph BnO2C
BnO2C
DCM, rt, 1.5 h
2. Toluene
8a R = H
1a R = H
9a R = H
EtO2C
Ph
8b R = Me
8c R = Ph
1b R = Me
1c R = Ph
9b R = Me
9c R = Ph
Entry Allene Reaction conditions (Second step)
Product (overall yield %)
1
2
3
4
5
7
8
9
10
11
12
13
14
15
16
17
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1c
rt, 48 ha
8a (59%)
8a (35%)
8a (54%)
9a (57%)
9a (38%)
rt, 6 db
50 ꢀC, 17 hb
120 ꢀC, 48 ha
60 h, 120 ꢀC
b
MW, 60 ꢀC, 10 minþ120 ꢀC, 3 mina 8a (79%)
MW, 120 ꢀC, 4 mina
MW, 200 ꢀC, 15 mina,c
120 ꢀC, 48 ha
8a (44%)
9a (62%)
8b (25%)
8b (25%)þ9b (13%)
120 ꢀC, 5 da
Table 5
MW, 60 ꢀC, 10 minþ120 ꢀC, 3 mina 8b (24%)
Reaction of nitrone 2a with methyl propiolate
MW, 120 ꢀC, 10 min
MW, 200 ꢀC, 15 mina,c
120 ꢀC, 3.5 ha
8b (28%)
9b (36%)
8c (36%)
8c (37%)
9c (26%)
1. MeNHOH.HCl
Base
Me
N
Me
N
BnO2C
Me
R1
Me
R1
R2
DCM, rt, 1.5 h
O
MW, 120 ꢀC, 5 min
MW, 200 ꢀC, 15 mina,c
•
2. Toluene
MeO2C
BnO2C
R2
BnO2C
a
1.5 equiv of ethyl phenylpropiolate.
1 equiv of ethyl phenylpropiolate.
Carried out in trichlorobenzene.
10a R1 = CO2Me; R2 = H 11a R1 = CO2Me; R2 = H
10b R1 = H; R2 = CO2Me 11b R1 = H; R2 = CO2Me
1a
b
c
Entry
Reaction conditions (Second step)
Products (overall yield %)
Pyrrole 9a was also obtained by thermolysis of 4-isoxazoline 8a.
1
2
3
4
5
6
7
8
9
6.5 h, rt
11b (43%)
11b (31%)
In fact, heating at reflux a solution of compound 8a in toluene
afforded pyrrole 9a in 54% yield via the 4-isoxazoline-pyrrole
rearrangement (Scheme 3).
Nitrone 2b also reacted with ethyl phenylpropiolate in a regio-
selective fashion (Table 4). In this case, the reaction carried out at
room temperature did not lead to the expected 1,3-dipolar cyclo-
adduct. However, 4-isoxazoline 8b could be isolated in 25% overall
yield when the reaction was performed at 120 ꢀC for 48 h (entry
6 d, rt
2 h, 50 ꢀC
2.5 h, 120 ꢀ
10a/10b (40%)
11a (58%)þ11b (9%)
11a (58%)
10a/10b (47%)
10a/10b (32%)þ11a (14%)
11a (23%)
C
20 h, 120 ꢀC
MW, 50 ꢀC, 2 min
MW, 60 ꢀC, 1 min
MW, 150 ꢀC, 15 min
MW, 200 ꢀC, 15 mina
11a (35%)
a
Carried out in trichlorobenzene.

S.M.M. Lopes et al. / Tetrahedron 66 (2010) 6078e6084
6081
In the NOESY spectrum of pyrrole 11b connectivity was ob-
served between the methyl protons at N-1 and the proton at C-5
confirming the structural assignment.
the two possible pathways depicted in Scheme 6. However, tran-
sition states could only be found for the pathway involving the
generation of 2-acylaziridine 14 (pathway A).
The 1,3-dipolar cycloaddition of nitrone 2a with butadienoate 1a
was also examined (Scheme 4). Carrying out the reaction in refluxing
toluene led to a complex mixture. Padwa et al. have described the
reaction of N-methyl-C-phenylnitrone with allenes and observed the
formation of estereoisomeric mixtures of methyleneisoxazolidine
derivatives, which undergo rearrangement to corresponding 4-iso-
xazoles on treatment with n-butyllithium.14 Accordingly, the re-
action of nitrone 2a with butadienoate 1a was performed at room
temperature for 4 h, followed by treatment with a solution of
n-butyllithium in hexane, which gave the corresponding 4-isoxazo-
line 12 in a regioselective fashion in 42% overall yield.
H
N
O
H
N
H
H
Pathway A
Pathway B
N
N
O
O
O
13
14
15
H
N
O
H
N
O
13
16
Scheme 6.
15
The quantum chemical calculations were performed with
Gaussian 0316 at the DFT level of theory, using the standard 6-31G
Me
N
1. MeNHOH.HCl
Base
*
BnO2C
Me
BnO2C
basis set17 and the three-parameter density functional B3LYP, which
includes Becke’s gradient exchange correction18 and the Lee, Yang
and Parr correlation functional.19 Full geometry optimizations were
performed for molecules 13e15 and true minima were confirmed
through vibrational analysis. Four different conformers were found
for structures 14 and 15 by performing relaxed scans on the potential
energy surface along the relevant coordinates. An exhaustive tran-
sition state search was carried out, with the eigenvector following
(EF) option, between all minima found in the potential energy sur-
face. All transition states found were characterized by having only
one imaginary frequency (see Supplementary data). The calcula-
tions of the intrinsic reaction coordinate (IRC) were performed to
check whether the transition states under consideration connect the
expected reactants and products.
•
DCM, rt, 1.5 h
O
CO2Bn
2. 1a, Toluene, rt, 4 h
3. THF, - 78ºC, n-BuLi
1a
Me
12 42%
Scheme 4.
The formation of 4-isoxazolines and pyrroles from allenoates
can be explained as outlined in Scheme 5. The initial 1,3-dipolar
cycloaddition of the nitrones generated from allenoates affords the
target 4-isoxazolines. These heterocycles undergo thermal rear-
rangement isomerization to 2-acylaziridines via NeO bond cleav-
age. The corresponding azomethine ylides, generated via
conrotatory aziridine ring opening undergo a proton shift followed
by 5-exo-trig cyclization leading to 2,3-dihydro-1H-pyrroles, which
are converted into 1H-pyrroles via dehydration.
The potential energy profile for thermal isomerization of
4-isoxazoline (13) to azomethine ylide 15 is shown in Figure 1.
R
CO2Bn
R1
R2
R
1,3-dipolar
MeNHOH
O
CO2Bn
cycloaddition
•
N
Me
R
Me
CO2Bn
R2
R1
N
O
ring contraction
Me
N
R
Me
N
Me
N
5-exo-trig
R
R
Me
N
R
R1
R2
cyclization
R1
H-shift
R1
R2
COR2
R1
OH
BnO2C
O
BnO2C
R2
BnO2C
Me
O
CO2Bn
R
- H2O
N
R1
BnO2C
R2
Scheme 5.
This is the most general reactivity pattern of 4-isoxazolines bear-
ing a methyl or methylene group at C-3. However, thermally induced
conversionof4-isoxazolines into azomethineylides via an alternative
mechanism has been proposed. In fact, the formation of stable azo-
methine ylides from isoxazolo[3,2-a]isoquinolines has been ratio-
nalized considering a mechanism involving consecutive C3eC4 bond
heterolysis and 1,3-sigmatropic shift rather than the accepted
mechanism pathway involving acylaziridines as intermediates.15
Therefore, we decided to study the isomerization of the parent
system 13 carrying out quantum chemical calculations, conducting
a very thorough search for the transition states corresponding to
As it can be seen, the ring contraction of 4-isoxazoline to 2-
acylaziridine is a very favourable process. On the other hand, the
aziridine and the 1,3-dipole resulting from the aziridine ring
opening have similar potential energy. The generation of the
azomethine ylide is always followed by a stabilizing process ei-
ther a ring closure to oxazoline or a proton shift followed by
cyclization leading to pyrroles (for derivatives having a methyl
or methylene group at C-4).7 Thus, the quantum chemical cal-
culations corroborate the favourability of the 4-isoxazoline
rearrangement to five-membered heterocycles via 2-acylazir-
idine intermediates.

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S.M.M. Lopes et al. / Tetrahedron 66 (2010) 6078e6084
4.2.1. Nitrone 2a. Nitrone 2a was obtained as a colourless oil (86%);
1H NMR 2.16 (3H, s), 3.62 (2H, s), 3.73 (3H, s), 5.16 (2H, s), 7.27e7.37
(5H, m, ArH); 13C NMR 19.7, 38.4, 47.7, 66.9, 128.3, 128.4, 128.6,
128.8, 135.6, 168.3.
4.2.2. Nitrone 2b. Nitrone 2b was obtained as a colourless oil
(88%); 1H NMR 1.14 (3H, t, J¼7.6 Hz), 2.41 (1H, q, J¼7.6 Hz),
2.61e2.91 (1H, m), 2.27 (1H, br d), 3.55 (1H, br s), 3.72 (3H, s), 5.16
(2H, s), 7.27e7.36 (5H, m, ArH).
4.2.3. Nitrone 2c. Nitrone 2c was obtained as a colourless oil (89%);
1H NMR 3.51 (2H, br s), 3.82 (3H, s), 3.86 (2H, s), 5.12 (2H, s),
7.12e7.43 (10H, m, ArH).
4.3. General procedure for the synthesis of 4-isoxazoles and
pyrroles from allenoates
Method A. Nitrone 2 (1 mmol) was dissolved in toluene (5 mL)
and the appropriate dipolarophile (1.73 mmol) was added. The
mixture was then stirred at room temperature or at reflux and the
reaction monitored by TLC. After the reaction was completed,
the solvent was evaporated off and the product purified by flash
chromatography [ethyl acetate/hexane].
Figure 1. Potential energy profile for thermal isomerization of 4-isoxazoline 13 to
azomethine ylide 15 calculated at B3LYP/6-31G* level of theory.
Method B. A solution of nitrone 2 (1 mmol) in toluene or 1,2,4-
TCB (2 mL) and the appropriate dipolarophile (1.73 mmol) was ir-
radiated in a microwave reactor (CEM Focused Synthesis System,
Discover S-Class) for 1 min with the temperature set to 60 ꢀC for the
synthesis of 4-isoxazolines 3 and 6, 4e10 min at 120 ꢀC for com-
pounds 8, 2 min at 50 ꢀC for compounds 10 and 15 min at 200 ꢀC for
pyrroles 5, 7, 9 and 11a. The solvent was removed under reduced
pressure and the crude product was purified by flash chromatog-
raphy [ethyl acetate/hexane].
3. Conclusion
A deeper insight into the synthesis of 4-isoxazolines via 1,3-
dipolar cycloaddition of nitrones generated from allenoates and the
subsequent thermal rearrangement to pyrroles is reported. The
cycloaddition of nitrones and alkynes carried out under mild con-
ditions led to 4-isoxazolines, whereas, forcing the reaction condi-
tions the corresponding pyrroles are obtained. The synthetic
methodology was successful using conventional reaction condi-
tions or under microwave irradiation.
4.3.1. Dimethyl 3-(2-(benzyloxy)-2-oxoethyl)-2,3-dimethyl-2,3-dihy-
droisoxazole-4,5-dicarboxylate (3). Compound 3 was purified by
flash chromatography [ethyl acetate/hexane (1:2)] and obtained as
an oil. Yield: Method A 66% and Method B 78%. IR (film) 1117, 1209,
1318, 1437, 1648, 1713, 1739, 2954 cmꢁ1; 1H NMR 1.52 (3H, s), 2.71
(1H, d, J¼14.4 Hz), 2.82 (3H, s), 2.98 (1H, d, J¼14.4 Hz), 3.68 (3H, s),
3.86 (3H, s), 5.11 (2H, s), 7.26e7.37 (5H, m, ArH); 13C NMR 19.1, 39.0,
42.8, 51.7, 53.1, 65.4, 66.5, 71.5,112.6,126.9,128.1,128.3,128.5,128.6,
135.8, 151.7, 159.6, 162.9, 169.6; MS (ESI) m/z 364 (MHþ, 34%), 315
(2) and 229 (2). HRMS (ESI) m/z 364.13759 (C18H22NO7 [MHþ],
364.13908).
Quantum chemical calculations indicate the favourability of the
parent system (4-isoxazoline) rearrangement to five-membered
heterocycles via 2-acylaziridine intermediates.
4. Experimental section
4.1. General
1H NMR spectra were recorded on a Bruker Avance III in-
strument operating at 400 MHz. 13C NMR spectra were recorded on
a Bruker Avance III instrument operating at 100 MHz. The solvent is
deuteriochloroform. IR spectra were recorded on a Perkin Elmer
1720X FTIR spectrometer. Mass spectra were recorded under elec-
tron impact (EI) or electrospray ionization (ESI). HRMS spectra were
recorded on a Finnigan MAT95 S instrument. Mp were recorded on
a Reichert hot stage and are uncorrected. Flash column chroma-
tography was performed with Merck 9385 silica as the stationary
phase.
4.3.2. 4-Benzyl 2,3-dimethyl 3-hydroxy-1,5-dimethyl-2,3-dihydro-
1H-pyrrole-2,3,4-tricarboxylate (4). Compound 4 was purified by
flash chromatography [ethyl acetate/hexane (1:1)] and obtained as
a white solid. Yield: Method A 56%. Mp 141.8e143.0 ꢀC (from ethyl
acetate/hexane). IR (KBr) 1169, 1216, 1594, 1680, 1745, 3485 cmꢁ1
;
1H NMR 2.36 (3H, s), 2.93 (3H, s), 3.65 (3H, s), 3.78 (3H, s), 3.96 (1H,
s, OH), 4.44 (1H, s), 5.00 (1H, d, J¼12.4 Hz), 5.21 (1H, d, J¼12.4 Hz),
7.26e7.35 (5H, m, ArH); 13C NMR 12.6, 32.5, 52.4, 53.4, 60.4, 64.8,
74.3, 81.1, 100.5, 127.8, 128.1, 128.4, 136.9, 164.5, 165.0, 166.9, 173.8;
MS (ESI) m/z 364 (MHþ, 30%), 346 (14) and 315 (6). HRMS (ESI) m/z
364.13989 (C18H22NO7 [MHþ], 364.13908).
4.2. General procedure for the synthesis of nitrones 2
To a stirred solution of allene (1.15 mmol) and N-methylhy-
droxylamine hydrochloride (1.26 mmol) in CH2Cl2 (40 mL) tri-
ethylamine (2.87 mmol) or NaHCO3 (11.5 mmol) was added at room
temperature. The reaction mixture was stirred for 90 min (syn-
thesis of nitrones 2a and 2b) or stirred overnight (synthesis of
nitrone 2c). The organic layer was washed with water, dried over
anhydrous Na2SO4 and the solvent evaporated off to give nitrones 2,
which were used without purification.
4.3.3. 4-Benzyl
2,3-dimethyl
1,5-dimethyl-1H-pyrrole-2,3,4-tri-
carboxylate (5). Compound 5 was purified by flash chromatography
[ethyl acetate/hexane (1:1)] and obtained as a white solid. Yield:
Method B 46%. Mp 103.8e104.9 ꢀC (from ethyl acetate/hexane). IR
(KBr) 1113, 1157, 1259, 1553, 1701, 1743 cmꢁ1; 1H NMR 2.56 (3H, s),
3.57 (3H, s), 3.79 (3H, s), 3.84 (3H, s), 5.23 (2H, s), 7.32e7.38 (5H, m,
ArH); 13C NMR 11.4, 32.7, 51.8, 52.3, 66.3, 110.3, 119.1, 125.8, 128.2,
128.4, 128.5, 135.8, 141.7, 160.3, 163.1, 166.8; MS (EI) m/z 345 (Mþ,

S.M.M. Lopes et al. / Tetrahedron 66 (2010) 6078e6084
6083
11%), 238 (100), 222 (67), 211 (20), 180 (27), 149 (21) and 91 (85).
by flash chromatography [ethyl acetate/hexane (1:5)] and obtained
as oil. Yield: Method A 25% and Method B 28%. IR (film) 696, 1107,
1302, 1375, 1447, 1598, 1635, 1691, 1736, 2978 cm1; 1H NMR 1.01
(3H, t, J¼7.2 Hz), 1.06 (3H, t, J¼7.2 Hz), 1.76e1.85 (1H, m), 2.04e2.14
(1H, m), 2.80 (1H, d, J¼14 Hz), 2.93 (3H, s), 3.02 (1H, d, J¼14 Hz),
4.04 (2H, q, J¼7.2 Hz), 5.08 (2H, s), 7.31e7.43 (8H, m, ArH) 7.52e7.54
(2H, m, ArH); 13C NMR 9.2, 13.8, 28.5, 37.8, 40.0, 59.7, 66.4, 75.0,
104.8, 127.7, 128.1, 128.2, 128.4, 129.5, 130.5, 135.9, 163.0, 164.3,
170.6. MS (ESI) m/z 410 (MHþ, 100%), 262 (3) and 201 (3). HRMS
(ESI) m/z 410.19623 (C24H28NO5 [MHþ], 410.19620).
HRMS (EI) m/z 345.1205 (C18H19NO6 [Mþ], 345.3466).
4.3.4. Dimethyl 3-(2-benzyloxy-2-oxoethyl)-3-ethyl-2-methyl-2,3-
dihydroisoxazole-4,5-dicarboxylate (6a). Compound 6a was purified
by flash chromatography [ethyl acetate/hexane (1:2)] and obtained
as an oil. Yield: Method A 42% and Method B 56%. IR (film) 699, 1112,
1170, 1317, 1437, 1646, 1712, 1751, 3447 cmꢁ1 1H NMR 0.97 (3H, t,
;
J¼7.6 Hz), 1.73e1.82 (1H, m), 1.92e2.01 (1H, m), 2.74 (1H, d,
J¼14.8 Hz), 2.91 (3H, s), 2.97 (1H, d, J¼14.8 Hz), 3.65 (3H, s), 3.86 (3H,
s), 5.09 (2H, s), 7.29e7.37 (5H, m, ArH); 13C NMR 8.9, 28.5, 38.3, 39.6,
51.7, 53.1, 53.5, 66.6, 74.7,110.6,128.2,128.3,128.5,135.7,152.0,159.5,
163.1,169.9; MS (ESI) m/z 378 (MHþ,100%), 306 (12), 288 (8) and 233
(6). HRMS (ESI) m/z 378.15549 (C19H24NO7 [MHþ], 378.15473).
4.3.10. Ethyl 3-benzyl-3-(2-benzyloxy-2-oxoethyl)-2-methyl-5-phe-
nyl-2,3-dihydroisoxazole-4-carboxylate (8c). Compound 8c was
purified by flash chromatography [ethyl acetate/hexane (1:4)]
and obtained as oil. Yield: Method A 36% and Method B 37%. IR
4.3.5. Dimethyl 3-benzyl-3-(2-benzyloxy-2-oxoethyl)-2-methyl-2,3-
dihydroisoxazole-4,5-dicarboxylate (6b). Compound 6b was puri-
fied by flash chromatography [ethyl acetate/hexane (1:2)] and
obtained as oil. Yield: Method A 55% and Method B 52%. IR (film)
(film) 697, 1110, 1153, 1375, 1689, 1735, 3031 cmꢁ1 1H NMR 1.01
;
(3H, t, J¼7.2 Hz), 2.83 (3H, s), 2.94 (1H, d, J¼15.6 Hz), 3.19 (1H, d,
J¼15.6 Hz), 3.21 (1H, d, J¼14 Hz), 3.26 (1H, d, J¼14 Hz),
3.88e3.96 (1H, m), 3.98e4.06 (1H, m), 5.10 (s, 2H), 7.16e7.37
(15H, m, ArH); 13C NMR 13.8, 38.2, 39.2, 43.7, 59.7, 66.6, 74.9,
105.2, 126.5, 127.6, 128.2, 128.4, 128.5, 129.4, 130.4, 131.4, 135.6,
135.8, 163.1, 164.2, 170.5. MS (ESI) m/z 472 (MHþ, 100%), 291 (5)
and 201 (7). HRMS (ESI) m/z 472.21128 (C29H30NO5 [MHþ],
472.21185).
700, 1101, 1167, 1313, 1437, 1717, 1734, 1752, 2953 cmꢁ1 1H NMR
;
2.77 (3H, s), 2.81 (1H, d, J¼15.6 Hz), 3.07 (1H, d, J¼15.6 Hz), 3.17
(2H, s), 3.58 (3H, s), 3.84 (3H, s), 5.10 (2H, s), 7.23e7.37 (10H, m,
ArH); 13C NMR 37.4, 39.4, 43.4, 51.6, 53.1, 66.8, 74.3, 111.1, 126.8,
128.0, 128.3, 128.4, 128.5, 131.0, 135.5, 135.6, 152.1, 159.5, 163.1,
170.0. MS (ESI) m/z 440 (MHþ, 39%) and 201 (4). HRMS (ESI) m/z
440.17033 (C24H26NO7 [MHþ], 440.17038).
4.3.11. 4-Benzyl 2-ethyl 1,5-dimethyl-3-phenyl-1H-pyrrole-2,4-di-
carboxylate (9a). Compound 9a was purified by flash chromatog-
raphy [ethyl acetate/hexane (1:5)] and obtained as a white solid.
Yield: Method A 57% and Method B 62% mp 81.9e83.0 ꢀC (from ethyl
acetate/hexane). IR (KBr) 715, 1107, 1159, 1243, 1284, 1683,
1704 cmꢁ1; 1H NMR 0.79 (3H, t, J¼7.2 Hz), 2.59 (3H, s), 3.86 (3H, s),
3.92 (2H, q, J¼7.2 Hz), 5.00 (2H, s), 6.86e6.88 (2H, m, ArH),
7.16e7.25 (8H, m, ArH); 13C NMR 11.7, 13.3, 32.8, 59.8, 65.4, 112.4,
120.7, 126.4, 127.0, 127.5, 127.7, 128.1, 129.7, 133.8, 136.0, 136.7, 141.0,
161.7, 164.9; MS (EI) m/z 377 (Mþ, 27%), 286 (100), 240 (79), 198
(10), 127 (11) and 91 (31). HRMS (EI) m/z 377.1626 (C23H23NO4 [Mþ],
377.1627).
4.3.6. 4-Benzyl 2,3-dimethyl 5-ethyl-1-methyl-1H-pyrrole-2,3,4-tri-
carboxylate (7a). Compound 7a was purified by flash chromatog-
raphy [ethyl acetate/hexane (1:2)] and obtained as a white solid.
Yield: Method A 18% and Method B 35%. Mp 60.1e61.3 ꢀC (from ethyl
acetate/hexane). IR (KBr) 759, 1154, 1219, 1259, 1476, 1706,
1733 cmꢁ1
;
1H NMR 1.16 (3H, t, J¼7.2 Hz), 3.03 (2H, q, J¼7.2 Hz),
3.57 (3H, s), 3.78 (3H, s), 3.85 (3H, s), 5.22 (2H, s), 7.27e7.38 (5H, m,
ArH); 13C NMR. 13.0, 18.4, 32.5, 51.8, 52.3, 66.3, 109.6, 119.2, 125.9,
128.2, 128.4, 128.5, 135.8, 147.0, 160.3, 162.8, 166.8; MS (ESI) m/z 359
(Mþ, 8%), 252 (88), 236 (100), 204 (17), 194 (17), 135 (20) and 91
(100). HRMS (ESI) m/z 359.1370 (C19H21NO6 [Mþ], 359.1369).
4.3.12. 4-Benzyl 2-ethyl 5-ethyl-1-methyl-3-phenyl-1H-pyrrole-2,4-
dicarboxylate (9b). Compound 9b was purified by flash chroma-
tography [ethyl acetate/hexane (1:5)] and obtained as a white solid.
Yield: Method A 13% and Method B 36%. Mp 61.7e63.6 ꢀC (from ethyl
acetate/hexane). IR (KBr) 735, 1105, 1157, 1243, 1513, 1683, 1704,
4.3.7. 4-Benzyl 2,3-dimethyl 5-benzyl-1-methyl-1H-pyrrole-2,3,4-
tricarboxylate (7b). Compound 7b was purified by flash chroma-
tography [ethyl acetate/hexane (1:2)] and obtained as a white solid.
Yield: Method A 37% and Method B 39%. Mp 127.4e128.6 ꢀC (from
ethyl acetate/hexane). IR (KBr) 746, 1109, 1143, 1240, 1509, 1701,
2980 cmꢁ1
;
1H NMR 0.79 (3H, t, J¼7.2 Hz), 1.22 (3H, t, J¼7.6 Hz),
1717, 1729, 3031 cmꢁ1
;
1H NMR 3.59 (3H, s), 3.74 (3H, s), 3.79 (3H,
3.05 (2H, q, J¼7.6 Hz), 3.88 (3H, s), 3.92 (2H, q, J¼7.2 Hz), 5.01 (2H,
s), 6.87 (2H, d, J¼7.2 Hz, ArH), 7.16e7.45 (8H, m, ArH); 13C NMR 13.4,
18.8, 32.6, 59.8, 65.4, 111.7, 120.8, 126.4, 127.0, 127.5, 127.7, 128.1,
129.7, 133.8, 136.0, 136.7, 146.4, 161.8, 164.6. MS (ESI) m/z 392 (MHþ,
57%), 378 (13) and 201 (3). HRMS (ESI) m/z 392.18582 (C24H26NO4
[MHþ], 392.18563).
s), 4.48 (2H, s), 5.22 (2H, s), 7.05e7.07 (2H, m, ArH), 7.18e7.33 (8H,
m, ArH); 13C NMR 30.7, 33.1, 51.9, 52.3, 66.5,111.2,119.9,126.7,128.0,
128.5, 128.5, 128.8, 135.6, 136.6, 142.8, 160.2, 163.0, 166.7. MS (ESI)
m/z 422 (MHþ, 25%), 259 (4), 247 (3) and 201 (5). HRMS (ESI) m/z
422.15948 (C24H24NO6 [MHþ], 422.15981).
4.3.8. Ethyl 3-(2-benzyloxy-2-oxoethyl)-2,3-dimethyl-5-phenyl-2,3-
dihydroisoxazole-4-carboxylate (8a). Compound 8a was purified by
flash chromatography [ethyl acetate/hexane (1:3)] and obtained as
a white solid. Yield: Method A 59% and Method B 44%. Mp
67.7e68.3 ꢀC (from ethyl acetate/hexane). IR (KBr) 761, 1118, 1290,
4.3.13. 4-Benzyl 2-ethyl 5-benzyl-1-methyl-3-phenyl-1H-pyrrole-
2,4-dicarboxylate (9c). Compound 9c was purified by flash chro-
matography [ethyl acetate/hexane (1:4)] and obtained as a white
solid. Yield: Method B 26%. Mp 117.8e120.2 ꢀC (from ethyl acetate/
hexane). IR (KBr) 705, 1105, 1241, 1500, 1686, 1706 cmꢁ1 1H NMR
;
1342, 1639, 1685, 1727 cmꢁ1
;
1H NMR 1.09 (3H, t, J¼7.2 Hz), 1.58
0.79 (3H, t, J¼7.2 Hz), 3.75 (3H, s), 3.93 (2H, q, J¼7.2 Hz), 4.50 (2H, s),
5.00 (2H, s), 6.81 (2H, d, J¼6.8 Hz, ArH), 7.11e7.45 (13H, m, ArH); 13C
NMR 13.3, 31.1, 33.2, 59.9, 65.6, 113.4,121.4, 126.4, 126.5, 127.1, 127.5,
127.7, 128.1, 128.1, 128.7, 129.8, 133.7, 135.8, 136.6, 137.5, 142.1, 161.7,
164.7. MS (ESI) m/z 454 (MHþ, 34%), 259 (8) and 201 (7). HRMS (ESI)
m/z 454.20100 (C29H28NO4 [MHþ], 454.20128).
(3H, s), 2.79 (1H, d, J¼14 Hz), 2.84 (3H, s), 3.01 (1H, d, J¼14 Hz), 4.07
(2H, q, J¼7.2 Hz), 5.11 (2H, s), 7.27e7.44 (8H, m, ArH), 7.54e7.56 (2H,
m, ArH); 13C NMR 13.8, 19.5, 38.8, 43.4, 59.8, 66.3, 71.8, 106.6, 127.7,
128.0, 128.1, 128.2, 128.4, 129.5, 130.6, 136.0, 162.7, 164.1, 170.3; MS
(ESI) m/z 396 (MHþ, 100%), 359 (3), 306 (7) and 246 (4). HRMS (ESI)
m/z 396.18156 (C23H26NO5 [MHþ], 396.18055).
4.3.14. Methyl 3-(2-benzyloxy-2-oxoethyl)-2,3-dimethyl-2,3-dihy-
droisoxazole-4-carboxylate (10a) and methyl 3-(2-benzyloxy-2-
oxoethyl)-2,3-dimethyl-2,3-dihydroisoxazole-5-carboxylate
4.3.9. Ethyl 3-(2-benzyloxy-2-oxoethyl)-3-ethyl-2-methyl-5-phenyl-
2,3-dihydroisoxazole-4-carboxylate (8b). Compound 8b was purified

6084
S.M.M. Lopes et al. / Tetrahedron 66 (2010) 6078e6084
(10b). Compounds 10a and 10b were obtained as a mixture after
purification by flash chromatography [ethyl acetate/hexane
(1:2)]. Yield: Method A 40% and Method B 47%. IR (film) 1089,
1151, 1237, 1652, 1704, 1738 cmꢁ1. Major component: 1H NMR 1.51
(3H, s), 2.75 (1H, d, J¼14.4 Hz), 2.80 (3H, s), 2.93 (1H, d,
J¼14.4 Hz), 3.67 (3H, s), 5.06e5.14 (2H, m), 7.24 (1H, s), 7.33e7.36
(5H, m, ArH); 13C NMR 19.3, 39.4, 51.1, 66.3, 69.0, 100.7, 112.4,
128.1, 128.2, 128.3, 128.5, 128.6, 135.9, 153.2, 164.0, 170.0; MS (ESI)
m/z 306 (MHþ, 100%). HRMS (ESI) m/z 306.13333 (C16H20NO5
[MHþ], 306.13360).
Supplementary data
Computational data are available. Supplementary data for this
article can be found in the online version, at doi:10.1016/j.
tet.2010.06.010.
References and notes
1. Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; WILEY-VCH GmbH.
KgaA: Weinheim, 2004.
2. Ma, S. Chem. Rev. 2005, 105, 2829e2871.
3. Ma, S. Aldrichimica Acta 2007, 40, 91e102.
4. Hassan, H. H. A. M. Curr. Org. Chem. 2007, 4, 413e439.
4.3.15. 4-Benzyl 2-methyl 1,5-dimethyl-1H-pyrrole-2,4-dicarboxylate
(11a). Compound 11a was purified by flash chromatography [ethyl
acetate/hexane (1:3)] and obtained as a white solid. Yield: Method A
58% and Method B 35%. Mp 73.0e74.4 ꢀC (from ethyl acetate/hex-
ane). IR (KBr) 1055, 1230, 1259, 1694, 1730 cmꢁ1; 1H NMR 2.56 (3H,
s), 3.80 (3H, s), 3.85 (3H, s), 5.26 (2H, s), 7.30e7.42 (6H, m, ArH and
CH); 13C NMR 11.4, 32.5, 51.2, 65.5, 112.0, 119.3, 121.5, 127.9, 128.2,
128.5, 136.6, 142.3, 161.5, 164.4; MS (EI) m/z 287 (Mþ, 10%), 196
(100), 180 (71) and 91 (26). HRMS (EI) m/z 287.1161 (C16H17NO4
[Mþ], 287.1158).
5. Pinho e Melo, T. M. V. D. Curr. Org. Chem. 2009, 13, 1406e1431.
6. Select examples of generation of nitrones from allenes: (a) Padwa, A.; Bullock,
W. H.; Kline, D. N.; Perumattam, J. J. Org. Chem. 1989, 54, 2862e2869; (b)
Padwa, A.; Meske, M.; Ni, Z. Tetrahedron 1995, 51, 89e106; (c) Lathbury, D. C.;
Shaw, R. W.; Bates, P. A.; Hursthouse, M. B.; Gallagher, T. J. Chem. Soc., Perkin
Trans. I 1989, 2415e2424; (d) Buchlovic, M.; Man, S.; Potácek, M. Tetrahedron
2008, 64, 9953e9961; (e) Moran, J.; Pfeiffer, J. Y.; Gorelsky, S. I.; Beauchemin, A.
M. Org. Lett. 2009, 11, 1895e1898; (f) Buchlovic, M.; Man, S.; Kislitson, K.;
Mathot, C.; Potácek, M. Tetrahedron 2010, 66, 1821e1826.
7. Reviews on 4-isoxazolines: (a) Freeman, J. P. Chem. Rev. 1983, 83, 241e261; (b)
Pinho e Melo, T. M. V. D. Eur. J. Org. Chem. 2010, 3363e3376.
€
8. Grünanjer, P.; Vito-Finzi, P. Isoxazolines (Dihydroisoxazoles) Cap. 2 In. The
Chemistry of Heterocyclic Compouds; Taylor, E. C., Weissberger, A., Eds.; Jonh
Wiley & Sons: 1991; Vol. 49.
4.3.16. 3-Benzyl 4-methyl 1,2-dimethyl-1H-pyrrole-3,4-dicarboxylate
(11b). Compound 11b was purified by flash chromatography [ethyl
acetate/hexane (1:2)] and obtained as a white solid. Yield: Method A
43%. Mp 56.5e57.9 ꢀC (from ethyl acetate/hexane). IR (KBr) 1072,
1170, 1285, 1696, 1718 cmꢁ1; 1H NMR 2.37 (3H, s), 3.51 (3H, s), 3.17
(3H, s), 5.29 (2H, s), 7.06 (1H, s), 7.28e7.37 (3H, m, ArH), 7.42e7.44
(2H, m, ArH); 13C NMR 10.9, 34.1, 51.3, 66.2, 112.6, 114.8, 126.9, 127.9,
128.3, 128.4, 135.9,136.4, 164.6,164.9; MS (EI) m/z 287 (Mþ, 8%),180
(100), 166 (17), 164 (68), 150 (40), 121 (29) and 91 (74). HRMS (EI)
m/z 287.1168 (C16H17NO4 [Mþ], 287.1158).
9. Recent examples on the synthesis of 4-isoxazolines via 1,3-dipolar cycloaddi-
tion: (a) Heaney, F.; McCarthy, T.; Mahon, M.; McKee, V. Org. Biomol. Chem.
2005, 3, 4351e4361; (b) François, D.; Maden, A.; Murray, W. V. Org. Lett. 2004, 6,
1931e1934; (c) Lu, L.; Cao, W.; Chen, J.; Zhang, H.; Zhang, J.; Chen, H.; Wei, J.;
Deng, H.; Shao, M. J. Fluorine Chem. 2009, 130, 295e300; (d) Abbiati, G.; Arcadi,
A.; Marinelli, F.; Rossi, E.; Verdecchia, M. Eur. J. Org. Chem. 2009, 1027e1031; (e)
Cantagrel, F.; Pinet, S.; Gimbert, Y.; Chavant, P. Y. Eur. J. Org. Chem. 2005,
2694e2701; (f) Cskun, N.; Yilmaz, B. Synth. Commun. 2004, 34, 1617e1623; (g)
Wierschem, F.; Rück-Braun, K. Eur. J. Org. Chem. 2004, 2321e2324.
10. Selected examples on the synthesis of pyrroles from 4-isoxazolines: (a) Yang,
Y.; Ohno, M.; Eguchi, S. Tetrahedron 1993, 49, 823e832; (b) Zhao, B.-X.; Yu, Y.;
Eguchi, S. Tetrahedron 1996, 52, 12049e12060; (c) Zhao, B.-X.; Eguchi, S. J. Chem.
Soc., Perkin Trans. 1 1997, 2973e2977; (d) Murray, W. V.; François, D.; Maden, A.;
Turchi, I. J. Org. Chem. 2007, 72, 3097e3099.
4.3.17. Benzyl 3-(2-benzyloxy-2-oxoethyl)-2,3,5-trimethyl-2,3-dihy-
droisoxazole-4-carboxylate (12). The nitrone 2a (0.22 g, 1 mmol)
was dissolved in toluene (5 mL) and benzyl buta-2,3-dienoates 1a
(0.3 g, 1.73 mmol) was added. The mixture was then stirred at room
temperature for 4 h and the solvent was evaporated off. To a solu-
tion of the crude product in anhydrous tetrahydrofuran at ꢁ78 ꢀC
was slowly added 0.7 mL of a 2.5 M solution of n-butyllithium in
hexane. The resulting solution was warmed to 0 ꢀC, quenched by
the addition of a saturated aqueous ammonium chloride solution
and extracted with ether. The organic phase was washed with
water, dried over sodium sulfate and concentrated under reduced
pressure to give the compound 12, which was purified by flash
chromatography [ethyl acetate/hexane (1:5)] and obtained as an oil
11. For reviews on pyrrole see (a) Sundberg, R. J. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford,
1996; Vol. 2, pp 119e206; (b) Trofimov, B. A.; Sobenina, L. N.; Demenev, A. P.;
Mikhaleva, A. L. Chem. Rev. 2004, 104, 2481e2506; (c) Furstner, A. Angew. Chem.,
Int. Ed. 2003, 42, 3582e3603.
12. (a) Pinho e Melo, T. M. V. D.; Cardoso, A. L.; Palacios, F.; de los Santos, J. M.; Pais,
A. A. A.; Abreu, P. E.; Paixão, J. A.; Beja, A. M.; Silva, M. R. Tetrahedron 2008, 64,
8141e8148; (b) Lopes, S. M. M.; Matos Beja, A.; Ramos Silva, M.; Paixão, J. A.;
Palacios, F.; Pinho e Melo, T. M. V. D. Synthesis 2009, 2403e2407; (c) Lopes, S.
M. M.; Santos, B. S.; Palacios, F.; Pinho e Melo, T. M. V. D. ARKIVOC 2010, v,
70e81; (d) Cardoso, A. L.; Lopes, S. M. M.; Matos Beja, A.; Ramos Silva, M.; de
los Santos, J. M.; Pinho e Melo, T. M. V. D.; Palacios, F. Tetrahedron 2009, 65,
9116e9124; (e) Ribeiro Laia, F. M.; Pinho e Melo, T. M. V. D. Tetrahedron Lett.
2009, 50, 6180e6182.
13. Buta-2,3-dienoates were prepared via Wittig reaction of benzyl(triphenyl-
phosphoranylidene)acetate with ketenes following the general procedure de-
scribed in Pinho e Melo, T. M. V. D.; Cardoso, A. L.; Rocha Gonsalves, A. M. d’A.;
Costa Pessoa, J.; Paixão, J. A.; Beja, A. M. Eur. J. Org. Chem. 2004, 4830e4839.
14. Padwa, A.; Kline, D. N.; Koehler, K. F.; Matzinger, M.; Venkatramanan, M. K.
J. Org. Chem. 1987, 52, 3909e3917.
in 42% yield. IR (film) 697, 1094, 1384, 1636, 1696, 1734, 3447 cmꢁ1
;
1H NMR 1.47 (3H,s), 2.11 (3H, s), 2.68 (1H, d, J¼14.4 Hz), 2.74 (3H, s),
2.91 (1H, d, J¼14.4 Hz), 5.04 (1H, d, J¼12.4 Hz), 5.09 (1H, d,
J¼12.4 Hz), 5.14 (2H, s), 7.25e7.36 (10H, m, ArH); 13C NMR 13.1, 19.7,
39.1, 43.6, 65.6, 66.2, 70.4, 106.4, 128.1, 128.2, 128.5, 128.6, 136.0,
136.2, 164.4, 165.4, 170.3; MS (ESI) m/z 396 (Mþ, 100%), 376 (6), 246
(15) and 215 (24). HRMS (ESI) m/z 396.18215 (C23H26NO5 [Mþ],
396.18055).
15. Coskun, N.; Tunçman, S. Tetrahedron 2006, 62, 1345e1350.
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Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.
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Acknowledgements
Thanks are due to Fundação para a Ciência e a Tecnologia (FCT,
Project: PTDC/QUI/64470/2006; Grants: SFRH/BD/45128/2008 and
SFRH/BD/28844/2006) for financial support. We acknowledge the
Nuclear Magnetic Resonance Laboratory of the Coimbra Chemical
Centre (www.nmrccc.uc.pt), University of Coimbra for obtaining
the NMR data.
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