Reaction of 5-(1-bromo-2-aryl-vinyl)-3-methyl-4-nitro-isoxazoles and 1,3-dicarbonyl compounds

Article abstract of DOI:10.1016/j.tet.2009.04.058

The preparation of E-5-(1-bromo-2-aryl-vinyl)-3-methyl-4-nitro-isoxazoles and their reaction with 1,3-dicarbonyl compounds to give cyclopropanes or dihydrofurans is described.

Full text of DOI:10.1016/j.tet.2009.04.058

Tetrahedron 65 (2009) 5402–5408
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Reaction of 5-(1-bromo-2-aryl-vinyl)-3-methyl-4-nitro-isoxazoles
and 1,3-dicarbonyl compounds
*
Mauro F.A. Adamo , Surisetti Suresh, Linda Piras
Centre for Synthesis and Chemical Biology (CSCB), Department of Pharmaceutical and Medicinal Chemistry, The Royal College of Surgeons in Ireland,
123 St. Stephen’s Green, Dublin 2, Dublin, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of E-5-(1-bromo-2-aryl-vinyl)-3-methyl-4-nitro-isoxazoles and their reaction with 1,3-
dicarbonyl compounds to give cyclopropanes or dihydrofurans is described.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 12 January 2009
Received in revised form 3 April 2009
Accepted 17 April 2009
Available online 24 April 2009
Keywords:
Polyfunctional scaffold
Styrylisoxazoles
Dihydrofurans
Cyclopropanes
1. Introduction
As part of our programme of research devoted to the design and
preparation of novel polyfunctional scaffolds1–10 we considered the
3-Methyl-4-nitro-5-styrylisoxazoles 1 represent a class of poly-
functional scaffold, which hold excellent potential for the genera-
tion of diversity (Fig. 1).1–10 Compounds 1 can be readily prepared
from commercially available 3,5-dimethyl-4-nitro-isoxazole and
aromatic aldehydes.4 It has been shown that compounds 1 can be
considered as cinnamate equivalents where the 4-nitro-isoxazole
core can be hydrolyzed to give a carboxylate.2,3,8,11 It is noteworthy
that compounds 1 have enhanced reactivity compared to cinna-
mates due to the conjugation of the nitro group at position C-4 of
the isoxazole core. Furthermore, compounds 1 have two electro-
philic centers that can be selectively reacted. Enolates, which are
stabilized soft nucleophiles, react at the soft electrophilic center E2,
whereas hard nucleophiles such as hydroxide react exclusively at
the hard electrophilic center E1 (Fig. 1).1–3,8,11
preparation of compounds 2 (Fig. 1). Isoxazoles 2, in which a halide
is introduced on the exocyclic alkene, hold an additional electro-
philic center E3 (Fig. 1) that increases the number of their possible
synthetic applications.
For instance, the alkenyl halide moiety in scaffold 2 could be
employed in various transition metal-mediated C–C bond forming
reactions including Heck, Sonogashira and related reactions to
access dienes or enynes.12 Furthermore, the low aromaticity ren-
ders isoxazoles 2 useful intermediates, since they could be easily
manipulated to obtain functionally complex derivatives, namely
1,3-dicarbonyls,13 hydroxyketones,14 enaminoketones,14,15
alcohols,16 azirines,17 enamines and -hydroxynitriles,18 and poly-
g-amino
b
amino alcohols.19 It was envisaged that the presence of two con-
tiguous electrophilic centers E2 and E3 and a suitable leaving group
connected to E3 could enable compounds 2 to cyclize through
a Michael addition–cyclization protocol (Fig. 1). In this respect, 2
could serve as a precursor for the preparation of cyclopropanes 4 or
dihydrofurans 5 by reaction with suitable dinucleophiles, for
example, 1,3-dicarbonyl compounds (Fig. 2).
NO2
NO2
X
E3
N
N
O
E1
O
Ar
E1
E2
Ar
E2
1
2
2. Results and discussion
Figure 1. Polyfunctional scaffolds 1 and 2.
3-Methyl-4-nitro-5-styrylisoxazoles 1a–f were brominated to
give dibromo derivatives 6a–f using the procedure described by
Sarti-Fantoni.20 Compounds 6a–f were then treated with triethyl-
amine to give bromo styrylisoxazoles 2a–f in good yields (Table 1).
* Corresponding author. Tel.: þ353 1 4022208; fax: þ353 1 4022168.
E-mail address: madamo@rcsi.ie (M.F.A. Adamo).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.058

M.F.A. Adamo et al. / Tetrahedron 65 (2009) 5402–5408
5403
NO2
Ar
NO2
NO2
O
O
COR
CO2R'
X
+
O
N
R
N
N
R
OR'
O
O
O
R = OMe
R = Alkyl,
Aryl
COOR'
Ar
Ar
4
2
3
5
Figure 2. Retrosynthetic analysis for cyclopropanes 4 and dihydrofurans 5.
Table 2
Table 1
Synthesis of bromo substituted styrylisoxazoles 2a–f
Synthesis of cyclopropanes 7a–f
NO2
NO2 NO2
NO2
NO2
O
O
CO2Me
CO2Me
Br2
Et3N
DBU
THF, 0 °C, 30 min
Br
Ar
Br
Br
N
N
N
N
N
+
MeO
OMe
O
cyclohexane
heat, 1 h
Toluene, rt, 6 h
O
O
O
O
Ar
Ar
7a-f
Br
6a-f
Ar
Ar
E only
2a-f
3a
1a-f
2a-f
Entry
Ar
C6H5
p-MeC6H4
p-MeOC6H4
p-ClC6H4
Reactant
Product
% Yield (trans/cis)
Entry
Ar
Reactant
Product
Yield a(%)
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
7a
7b
7c
7d
7e
7f
88 (1:0)
98 (1:0)
92 (1:0)
78 (1:0)
70 (1:0)
d
1
2
3
4
5
6
C6H5
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
90
45
91
89
88
85
p-MeC6H4
p-MeOC6H4
p-ClC6H4
2-Pyridyl
2-Pyridyl
2-(5-Bromothiophenyl)
2-(5-Bromothiophenyl)
a
The products were pure enough that obviates chromatography. Yields de-
termined over two steps.
delight, the reaction gave cyclopropane 7a, exclusively, in excellent
yield and without the need of chromatographic purification. Im-
portantly, only one diastereomer was observed in this reaction and
a trans stereochemistry was assigned based on NOE studies. In
these experiments no enhancement was observed irradiating each
of the cyclopropyl C–H.
The exclusive formation of trans-7a was explained as follows
(Scheme 1). Initial Michael addition of 3a to 2a generated in-
termediate 8. Deprotonation of 8 gave enolate 9 (herein shown as
its conjugated anion), which underwent cyclization through an
intermolecular SN2 reaction. In this step, the nucleophile and the
bromide leaving group lay antiperiplanar, giving trans-7a as the
only product.
We then studied the scope of this reaction by reacting bromo
styrylisoxazoles 2a–f and dimethyl malonate 3a (Table 2). The re-
action of 3a and bromo styrylisoxazoles 2b,c gave the corre-
sponding cyclopropanes trans-7b–d in excellent yields (Table 2,
entries 2–4). Bromo styrylisoxazole 2e bearing a 2-pyrydyl sub-
stituent also gave the corresponding cylcopropane trans-7e in good
yield (Table 2, entry 5). Reaction of 2f and 3a did not give the
corresponding cyclopropane, but a complex reaction mixture.
With the objective to synthesize dihydrofurans (Fig. 2), we have
reacted bromo styrylisoxazole 2a and methyl acetoacetate 3b in the
presence of DBU in THF at 0 ꢀC (Scheme 2). Reaction of 2a and 3b
was completed in 30 min and furnished the desired dihydrofuran
10a in 50% yield. Dihydrofuran 10a was formed as an 8:2 mixture of
diastereoisomers, which were inseparable by silica gel chroma-
tography. The trans stereochemistry was assigned to the major
isomer of 10a by X-ray crystal structure analysis run on a pure
sample of trans-10a obtained by slow crystallization from methanol
(Fig. 4).23
Importantly, products 2a–f were obtained as a single isomer. The E
stereochemistry was assigned to 2d based on X-ray crystal struc-
ture analysis (Fig. 3).21 The nitro-isoxazole core is well-known to
enhance the acidity of the proton at C-5 hence stabilizing formation
of carbanions at this position. This rendered an E1cb mechanism
energetically favored and furnished a rational for the exclusive E
stereochemistry observed. It is noteworthy that
a-bromo cinna-
mates were not obtained as a single isomer from the reaction of
cinnamate esters in a bromination–dehydromination protocol.22
Additionally, in these reactions, Z-bromo cinnamates were
obtained as major isomers.
Initially, bromo styrylisoxazole 2a was reacted in THF with di-
methyl malonate 3a in the presence of DBU (Table 2, entry 1). To our
In addition, this reaction furnished cyclopropane 11a in 41%
yield (Scheme 2), which was obtained as a single diastereoisomer. It
is interesting to note that compound 11a contains three stereo-
centers including a quaternary one. The exclusive formation of 11a
could be explained as follows (Scheme 3). Michael addition of 3b to
2a generated intermediate 12. Deprotonation of 12 gave enolate 13
(herein shown as its conjugated anion), which underwent cycli-
zation through an intramolecular SN2 reaction. In this step, the
enolate nucleophile and the bromide leaving group lay anti-
periplanar, giving trans-11a as the only product.
Figure 3. ORTEP representation of crystal structure of 2d (thermal ellipsoids are
drawn at 30% probability).

5404
M.F.A. Adamo et al. / Tetrahedron 65 (2009) 5402–5408
H3CO2C
H
H3CO2C
H
CO2CH3
Ph
CO2CH3
Ph
H
Ph
Is
H3CO2C
H3CO2C
Is
3a
Ph
DBU
DBU
Br
Is
Is
H
Br
H
2a
8
Br
9
trans-7a
Scheme 1. Proposed mechanism for the formation of trans-7a.
NO2
Ph
NO2
NO2
NO2
O
O
COMe
CO2Me
DBU
O
O
Br
N
Me
N
Me
N
N
+
+
+
O
O
Me
OMe
O
O
THF, 0 °C, 30 min
CO2Me
CO2Me
10a- cis 10%
Ph
Ph
2a
Ph
11a 41%
3b
10a- trans 40%
Scheme 2. Reaction of 2a and methyl acetoacetate 3b.
Table 3
Reaction of 2a and 3b using different solvents and bases
Entry 3b (equiv) Base (equiv) Solvent % Yield of 10a % Yield of 11a
(trans/cis)
(trans/cis)
1
1
1
1
1
1
2
3
4
5
4
3
DBU (1)
DBU (1)
DBU (1)
Et3N (10)
DBU (2)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
THF
25 (8:2)
d
19 (1:0)
d
2a
3a
4b
5a
6
MeOH
THF/MeOH
THF
THF
THF
THF
THF
THF
EtOH
d
d
d
d
d
d
43 (8:2)
50 (8:2)
45 (8:2)
50 (8:2)
48 (2:8)
36 (1:0)
42 (1:0)
36 (1:0)
42 (1:0)
d
7
8
9
10
11
THF anhydrous 50 (8:2)
42 (1:0)
a
The reactant 2a was consumed completely.
The reactant 2a was recovered.
b
material 2a (Table 3, entry 4), while use of excess DBU (Table 3,
entry 5) lead to a complex reaction mixture.
The reaction of 2a with an excess of 3b in THF using 1 equiv of
DBU as the base gave dihyrofuran 10a and cyclopropane 11a in
moderate yields and with good to excellent stereoselectivity (Table
3, entries 6–9). It was interesting to observe a complete switch-over
in the stereoselectivity of 10a when the reaction of 2a and 3b was
carried out in ethanol (Table 3, entry 10).
Since there was an interesting stereochemical outcome in the
formation of 10a using THF and ethanol as solvents (Table 3,
compare entries 9 and 10), we considered to study the effect of
solvent in this reaction. Compound 10a, obtained using THF as
a solvent (Table 3, entry 9), was treated with DBU in different
solvents. The results are in given in Table 4. No change in the di-
astereomeric ratio was observed when 10a (trans/cis¼8:2) was
treated with DBU in solvents like n-hexane, 1,4-dioxane, CH3CN,
DMSO, and 2-propanol (Table 4, entries 1–5). The reaction of 10a
(trans/cis¼8:2) with DBU in methanol resulted in the enrichment
of diastereoisomeric ratio (trans/cis¼9.5:0.5) (Table 4, entry 6).
Interestingly, compound 10a (trans/cis¼8:2) provided 10a with
inverted diastereoisomeric ratio (trans/cis¼2:8) when reacted
Figure 4. ORTEP representation of crystal structure of dihydrofuran 10a (thermal
ellipsoids are drawn at 30% probability).
The stereoselective formation of the quaternary stereogenic
center in compound 11a could be explained considering a steric
clash occurring between the methoxyester and the phenyl group in
intermediate 13 (Scheme 3).
The reaction of 2a and 3b was conducted under various reaction
conditions in order to identify a set of conditions to obtain com-
pound 10a or 11a exclusively. In particular, the ratio of reactants,
solvent, amount of base, and temperature were studied (Table 3).
Unfortunately, these experiments gave dihydrofurans and cyclo-
propanes in similar amounts. Reaction of 2a with 1 equiv of 3b and
1 equiv of DBU in THF gave dihydrofuran 10a in 25% yield as a 8:2
trans/cis mixture accompanied by 19% of cyclopropane 11a (Table 3,
entry 1). When methanol was used, reactant 2a was completely
consumed; however a complex reaction mixture was formed (Table
3, entries 2 and 3). Use of Et3N in THF gave unreacted starting
H3CO2C
COCH3
H3CO2C
COCH3
H
Ph
Is
H3COC
3b
H
H
Ph
Ph
Ph
H3CO2C
Is
DBU
DBU
Br
Is
Br
Br
Is
H
H
2a
12
13
11a
Scheme 3. Proposed mechanism for the formation of 11a.

M.F.A. Adamo et al. / Tetrahedron 65 (2009) 5402–5408
5405
Table 4
Reaction of 10a with DBU (1 equiv) in different solvents
Entry
Starter (trans/cis)
Solvent
Product (trans/cis)
1
2
3
4
5
6
7
10a (8:2)
10a (8:2)
10a (8:2)
10a (8:2)
10a (8:2)
10a (8:2)
10a (8:2)
n-Hexane
1,4-Dioxane
CH3CN
10a (8:2)
10a (8:2)
10a (8:2)
10a (8:2)
10a (8:2)
10a (9.5:0.5)
10a (2:8)
DMSO
2-Propanol
Methanol
EtOH
with DBU in ethanol (Table 4, entry 7). This could be explained
considering that: (i) trans-10a and cis-10a possess different ther-
modynamic stability in different media; (ii) trans-10a and cis-10a
are in thermodynamic equilibrium under the experimental con-
ditions used. This was demonstrated by submitting a sample
containing cis-enriched 10a (trans/cis¼2:8) to reaction with DBU
in methanol. This reaction gave trans-enriched 10a (trans/
cis¼9.5:0.5) providing a rationale for the interconversion of trans-
10a to cis-10a.
We have next studied the reaction of different bromo styr-
ylisoxazoles 2a–f with methyl acetoacetate 3b (Table 5). The
reaction of 2a–d and methyl acetoacetate furnished dihy-
drofurans 10a–d in moderate yields and with good diaster-
eoselection. Cyclopropanes 11a–f were also obtained in
moderate yields and with excellent diastereoselectivity (Table 5,
entries 1–4). The relative stereochemistry for cyclopropanes
was assigned based on the single crystal X-ray structure analysis
of 11b24 and 11f25 (Figs. 5 and 6). The reaction of 2e, having
a 2-pyridyl group, gave cyclopropane 11e, exclusively (Table 5,
entry 5). The reaction of 2f, containing a 2-(5-bromothiophenyl)
substituent, and 3b gave dihydrofuran trans-10f exclusively
(Table 5, entry 6). In this latter example, the presence of a large
substituent provided a large difference in energy between trans-
10f and cis-10f and the most thermodynamically stable trans-
10f was formed exclusively.
Figure 5. ORTEP representation of crystal structure of dihydrofuran 11b; only one of
the two enantiomers was shown for clarity (thermal ellipsoids are drawn at 30%
probability).
In summary, we have described the preparation of a new
polyfunctional scaffolds 2a–f that has three electrophilic centers.
The reactivity of 2a–f toward dinucleophiles was then studied.
Reaction of 2a–f with malonate was shown as an efficient means to
prepare cyclopropanes trans-7a–e in high yields. The reaction of
2a–f with methyl acetoacetate allowed the preparation of dihy-
drofurans 10a–f and cyclopropanes 11a–f in moderate yields.
Cyclopropanes 11a–f with three chiral centers were obtained as
a single diastereoisomer. Considering the reactivity of cyclopro-
panes, dihydrofurans, and 4-nitro-isoxazoles it is easy to envisage
the potential of compounds 7 and 10,11 in organic synthesis.
Figure 6. ORTEP representation of crystal structure of dihydrofuran 11f; only one of
the two enantiomers was shown for clarity (thermal ellipsoids are drawn at 30%
probability).
Table 5
Reaction of 2a–f and methyl acetoacetate 3b
NO2
Ar
NO2
NO2
O
O
COMe
O
DBU
THF, 0 °C, 30 min
Br
N
Me
N
N
+
+
O
Me
OMe
O
CO2Me
O
CO2Me
Ar
11a-f
Ar
2a-f
3b
10a-f
Entry
Ar
C6H5
p-MeC6H4
p-MeOC6H4
p-ClC6H4
% Yield of 10 (trans/cis)
% Yield of 11
1
2
3
4
5
6
10a, 50 (8:2)
10b, 45 (8:2)
10c, 56 (8:2)
10d, 40 (8:2)
10e, d
11a, 42
11b, 29
11c, 35
11d, 36
11e, 50
11f, 10
2-Pyridyl
2-(5-Bromothiophenyl)
10f, 10 (1:0)

5406
M.F.A. Adamo et al. / Tetrahedron 65 (2009) 5402–5408
3. Experimental section
2H, J¼8.0 Hz), 7.64 (Ar–CH, s, 1H), 7.20 (Ar–H, d, 2H, J¼8.0 Hz), 2.53
(Is–CH3, s, 3H), 2.34 (Ar–CH3, s, 3H); 13C NMR (100.6 MHz): 167.15,
156.45, 141.31, 141.24, 131.0, 130.50, 130.11, 129.36, 100.14, 21.64,
11.88. Anal. Calcd for C13H11BrN2O3: C 48.32%, H 3.43%, N 8.67%.
Found: C 48.44%, H 3.61%, N 8.48%.
3.1. General experimental
1H and 13C NMR Spectra were recorded on a 200 or a 400 MHz
spectrometer at ambient temperatures. 1H NMR spectral assign-
ments are supported by 1H–1H COSY and 13C–1H COSY where
necessary. For 1H NMR recorded in CDCl3 chemical shifts (dH) are
quoted in parts per million (ppm) and are referenced to the residual
solvent peak. The following abbreviations are used: s, singlet, d,
doublet, t, triplet, dd, doublet of doublets, dt, doublet of triplets, tt,
triplet of triplets, m, multiplet; and br, broad. Coupling constants (J)
were recorded in hertz (Hz) to the nearest 0.5 Hz. Carbon spectra
are supported by DEPT analysis where necessary. Infrared (IR)
spectra were recorded as thin films between NaCl plates. Absorp-
tion maximum (nmax) was reported in wavenumbers (cmꢁ1) and
only selected peaks are reported. The following abbreviations are
used: w, weak; m, medium; s, strong; and br, broad. High resolution
mass spectra were obtained on a Waters Micro mass LCT and low
resolution mass spectra were recorded on Waters Micro mass
Quattro LCMS spectrometers at 70 eV. Elemental analysis was car-
ried out using a CE440 Elemental Analyser purchased from Exeter
Analytical (UK) Ltd. Flash chromatography was carried out using
silica gel 60 (0.040–0.063 mm, 230–400 mesh) as the stationary
phase. Thin layer chromatography was carried out on aluminum
backed plates pre-coated with silica gel 60, which were visualized
by quenching of UV fluorescence (lmax¼254 nm) or by staining
with either 10% w/v ammonium molybdate in 2 M sulfuric acid or
basic potassium permanganate solution (followed by heat) as ap-
propriate. Retention factors (Rf) are reported to ꢂ0.05.
3.2.3. 5-[1-Bromo-2-(4-methoxy-phenyl)-vinyl]-3-methyl-4-
nitro-isoxazole 2c
Yellow solid, mp 169–174 ꢀC (methanol), 1.54 g, 95% yield,
Rf¼0.36 (petroleum ether/EtOAc, 95:5); IR (KBr)/cmꢁ1: 3015 w,
2928 w, 2872 w, 1600 s, 1563 s; 1H NMR (400 MHz, CDCl3): 7.82
(Ar–H, d, 2H, J¼9.0 Hz), 7.64 (Ar–CH, s, 1H), 6.92 (Ar–H, d, 2H,
J¼9.0 Hz), 3.81 (Ar–OCH3, s, 3H), 2.53 (Is–CH3, s, 3H); 13C NMR
(100.6 MHz): 167.8, 161.5, 156.5, 140.9, 132.2, 130.9, 125.9, 114.9,
99.1, 55.5, 11.9. Anal. Calcd for C13H11BrN2O4: C 46.04%, H 3.27%, N
8.26%. Found: C 46.19%, H 3.31%, N 8.09%.
3.2.4. 5-[1-Bromo-2-(4-chloro-phenyl)-vinyl]-3-methyl-4-
nitro-isoxazole 2d
Yellow solid, mp 189–192 ꢀC (methanol), 1.53 g, 89% yield,
Rf¼0.31 (petroleum ether/EtOAc, 95:5); IR (KBr)/cmꢁ1: 2998 w,
2928 w, 2872 w, 1540 s; 1H NMR (400 MHz, CDCl3): 7.72 (Ar–H, d,
2H, J¼8.8 Hz), 7.61 (Ar–CH, s, 1H), 7.38 (Ar–H, d, 2H, J¼8.8 Hz), 2.54
(Is–CH3, s, 3H); 13C NMR (100.6 MHz): 166.7, 156.5, 140.0, 136.6,
131.7, 131.2, 130.8, 129.0, 102.1, 11.8. Anal. Calcd for C12H8BrClN2O3:
C 41.95%, H 2.35%, N 8.15%. Found: C 41.76%, H 2.19%, N 8.32%.
3.2.5. 2-[2-Bromo-2-(3-methyl-4-nitro-isoxazol-5-yl)-
vinyl]-pyridine 2e
Dark green solid, mp 201–202 ꢀC (methanol), 1.36 g, 88% yield,
Rf¼0.24 (petroleum ether/EtOAc, 75:25); IR (KBr)/cmꢁ1: 2999 w,
2938 w, 2870 w, 1554 s; 1H NMR (400 MHz, CDCl3): 8.66 (Py–H, m,
1H), 8.04 (Py–H, d, 1H, J¼8.0 Hz), 7.78 (Py–H, m, 1H), 7.75 (Py–CH, s,
1H), 7.30 (Py–H, m, 1H), 2.55 (Is–CH3, s, 3H); 13C NMR (100.6 MHz):
166.5, 156.4, 152.1, 149.8, 140.5, 136.6, 130.5, 125.0, 124.4, 104.4, 11.8;
HRMS: m/z found [MþH]þ 309.9837, C11H9BrN3O3 requires
309.9827, m/z: 309 (100%, [MþH]þ). Anal. Calcd for C11H8BrN3O3: C
42.60%, H 2.60%, N 13.55%. Found: C 42.79%, H 2.65%, N 13.35%.
3.2. Typical experimental procedure for the preparation of 2a–f
A suspension of styrylisoxazoles 1a–f (4 mmol) in cyclo-
hexane (40 mL) was heated to reflux with a heat gun until
a
homogeneous solution was observed. Bromine (4 mmol,
640 mg) was added drop wise and the mixture was slowly
cooled down to room temperature and stirred for 30 min. The
solution was quenched with 10% aqueous Na2S2O3 solution
(40 mL) and extracted with CH2Cl2 (2ꢃ50 mL). The combined
organic extracts were dried over anhydrous Na2SO4, filtered,
and the solvent was removed under vacuum. The crude
dibromides 6a–f thus obtained were used in the next reaction
without further purification. Dibromides 6a–f (4 mmol) were
taken in toluene (40 mL) and added Et3N (20 mmol, 4.2 mL) at
room temperature. The reaction mixture was stirred at rt for
8 h. After this time toluene was removed under reduced pres-
sure. The crude was diluted with dichloromethane (30 mL) and
it was washed with 3 N HCl (10 mL), water (20 mL), and brine
(10 mL). The organic phase was separated, dried over anhy-
drous Na2SO4, filtered, and concentrated to dryness to give
products 2a–f.
3.2.6. 5-[1-Bromo-2-(5-bromothiophen-2-yl)-vinyl]-3-methyl-4-
nitro-isoxazole 2f
Brown solid, mp 158–160 ꢀC (methanol),1.67 g, 85% yield, Rf¼0.30
(petroleum ether/EtOAc, 90:10); IR (KBr)/cmꢁ1: 3010 w, 2930w, 2852
w, 1533 s; 1H NMR (400 MHz, CDCl3): 8.07 (Thiop–CH, s, 1H), 7.22
(Thiop–H, d, 1H, J1¼3.6 Hz), 7.10 (Thiop–H, d, 1H, J¼3.6 Hz), 2.52 (Is–
CH3, s, 3H); 13C NMR (100.6 MHz): 165.8, 156.9, 138.6, 135.8, 134.8,
131.1,130.1,120.2, 99.0,12.0. Anal. Calcd for C10H6Br2N2O3S: C 30.48%,
H 1.53%, N 7.11%. Found: C 30.28%, H 1.61%, N 7.23%.
3.3. Experimental procedure for the reaction of 2a–f
and dimethyl malonate
Isoxazoles 2a–f (0.5 mmol) and dimethyl malonate (1.5 mmol)
were taken in THF (5 mL) and added DBU (1.5 mmol) drop wise at
0 ꢀC. The reaction mixture was stirred at 0 ꢀC for 30 min. Then the
reaction mixture was diluted with EtOAc (10 mL) and washed with
3 N HCl (5 mL), water (10 mL), and brine (5 mL). The organic phase
was separated, dried over anhydrous Na2SO4, filtered, and concen-
trated to dryness to give a crude oil. The excess dimethyl malonate
was removed under high vacuum to obtain the product cyclopro-
panes 7a–f in pure form without need of column chromatography.
3.2.1. 5-(1-Bromo-2-phenyl-vinyl)-3-methyl-4-nitro-isoxazole 2a
Yellow solid, 1.39 g, 90% yield, mp 192–195 ꢀC (methanol),
Rf¼0.37 (petroleum ether/EtOAc, 95:5); IR (KBr)/cmꢁ1: 3010 w,
2928 w, 2870 w, 1561 s; 1H NMR (400 MHz, CDCl3): 7.77 (Ar–H, m,
2H), 7.66 (Ar–CH, s, 1H), 7.40 (Ar–H, m, 3H), 2.54 (Is–CH3, s, 3H); 13
C
NMR (100.6 MHz): 167.0, 156.4, 141.3, 133.3, 131.1, 130.6, 130.0,
128.6, 101.3, 11.9. Anal. Calcd for C12H9BrN2O3: C 47.23%, H 2.93%, N
9.06%. Found: C 47.05%, H 3.04%, N 8.95%.
3.2.2. 5-(1-Bromo-2-p-tolyl-vinyl)-3-methyl-4-nitro-isoxazole 2b
Yellow solid, 0.73 g, 45% yield, mp 178–180 ꢀC (methanol),
Rf¼0.30 (petroleum ether/EtOAc, 95:5); IR (KBr)/cmꢁ1: 3011 w,
2928 w, 2870 w, 1557 s; 1H NMR (400 MHz, CDCl3): 7.70 (Ar–H, d,
3.3.1. 2-(3-Methyl-4-nitro-isoxazol-5-yl)-3-phenyl-cyclopropane-
1,1-dicarboxylic acid dimethyl ester 7a
Yellow oil, 158 mg, 88% yield, Rf¼0.1 (petroleum ether/EtOAc,
95:5); IR (neat)/cmꢁ1: 2999 w, 2955 w, 2875 w, 1749 s, 1550 s; 1H

M.F.A. Adamo et al. / Tetrahedron 65 (2009) 5402–5408
5407
NMR (400 MHz, CDCl3): 7.25 (Ar–H, m, 5H), 4.19 (Is–CH, d, 1H,
J¼8.4 Hz), 3.89 (Ar–CH, d, 1H, J¼8.4 Hz), 3.67 (CO2CH3, s, 3H), 3.43
(CO2CH3, s, 3H), 2.51 (Is–CH3, s, 3H); 13C NMR (100.6 MHz): 167.57,
165.25, 163.94, 154.99, 131.03, 130.5, 127.56, 127.44, 127.25, 52.48,
52.05, 43.81, 35.28, 25.25, 10.59; HRMS: m/z found [MþNa]þ
383.0858, C17H16N2O7Na requires 383.0855, m/z: 383 (100%,
[MþNa]þ).
concentrated to dryness to give the crude. The crude was subjected
to column chromatography on silica gel using a mixture of petro-
leum ether and EtOAc (9:1) as an eluent to obtain dihyrofurans
10a–f and cyclopropanes 11a–f.
3.4.1. 2-Methyl-5-(3-methyl-4-nitro-isoxazol-5-yl)-4-phenyl-4,5-
dihydrofuran-3-carboxylic acid methyl ester 10a
Pale yellow solid, 86 mg, 50% yield, Rf¼0.2 (petroleum ether
/EtOAc, 95:5); IR (KBr)/cmꢁ1: 2971 w, 2878 w, 1725 s, 1534 s; for
trans isomer: 1H NMR (400 MHz, CDCl3): 7.23 (Ar–H, m, 5H), 5.99
(Is–CH, d, 1H, J¼4.0 Hz), 4.39 (Ar–CH, m, 1H), 3.51 (CO2CH3, s, 3H),
2.54 (Is–CH3, s, 3H), 2.38 (CH3–C–O, s, 3H); 13C NMR (100.6 MHz):
170.6, 168.3, 164.9, 156.0, 141.0, 130.2, 128.9, 127.8, 127.1, 107.1, 82.0,
54.1, 51.2, 14.0, 11.5; for cis isomer: 1H NMR (400 MHz, CDCl3): 7.03
(Ar–H, m, 3H), 6.87 (Ar–H, m, 2H), 6.39 (Is–CH, d,1H, J¼8.8 Hz), 4.90
(Ar–CH, d, 1H, J¼8.8 Hz), 3.49 (CO2CH3, s, 3H), 2.42 (Is–CH3, s, 3H),
2.22 (CH3–C–O, s, 3H); 13C NMR (100.6 MHz): 170.0, 155.1, 130.9,
128.4, 81.4, 52.6, 22.7, 11.0; HRMS: m/z found [MþNa]þ 367.0911,
C17H16N2O6Na requires 367.0906, m/z: 367 (100%, [MþNa]þ).
3.3.2. 2-(3-Methyl-4-nitro-isoxazol-5-yl)-3-p-tolyl-cyclopropane-
1,1-dicarboxylic acid dimethyl ester 7b
Yellow oil, 183 mg, 98% yield, Rf¼0.1 (petroleum ether/EtOAc,
95:5); IR (neat)/cmꢁ1: 3003 w, 2985 w, 2873 w, 1735 s, 1546 s; 1H
NMR (400 MHz, CDCl3): 7.12 (Ar–H, d, 2H, J¼8.4 Hz), 7.06 (Ar–H, d,
2H, J¼8.0 Hz), 4.16 (Is–CH, d, 1H, J¼8.4 Hz), 3.85 (Ar–CH, d, 1H,
J¼8.0 Hz), 3.66 (CO2CH3, s, 3H), 3.45 (CO2CH3, s, 3H), 2.50 (Is–CH3, s,
3H), 2.25 (Ar–CH3, s, 3H); 13C NMR (100.6 MHz): 167.7, 165.3, 164.0,
155.0, 137.0, 130.7, 128.2, 127.9, 127.3, 52.4, 52.1, 43.8, 35.1, 25.3, 20.1,
10.6; HRMS: m/z found [MþNa]þ 397.0996, C18H18N2O7Na requires
397.1012, m/z: 397 (100%, [MþNa]þ).
3.3.3. 2-(4-Methoxy-phenyl)-3-(3-methyl-4-nitro-isoxazol-5-yl)-
cyclopropane-1,1-dicarboxylic acid dimethyl ester 7c
3.4.2. 1-Acetyl-2-(3-methyl-4-nitro-isoxazol-5-yl)-3-phenyl-
cyclopropanecarboxylic acid methyl ester 11a
Yellow oil, 180 mg, 92% yield, Rf¼0.1 (petroleum ether/EtOAc,
75:25); IR (neat)/cmꢁ1: 2999 w, 2954 w, 1750 s, 1558 s; 1H NMR
(400 MHz, CDCl3): 7.16 (Ar–H, d, 2H, J¼8.0 Hz), 6.78 (Ar–H, d, 2H,
J¼8.0 Hz), 4.14 (Is–CH, d, 1H, J¼8.4 Hz), 3.83 (Ar–CH, d, 1H,
J¼8.4 Hz), 3.72 (CO2CH3, s, 3H), 3.66 (CO2CH3, s, 3H), 3.46 (Ar–
OCH3, s, 3H), 2.50 (Is–CH3, s, 3H); 13C NMR (100.6 MHz): 168.8,
166.4, 165.1, 159.5, 156.0, 131.0, 129.6, 123.9, 114.0, 55.3, 53.5, 53.1,
44.9, 35.9, 26.4, 11.6; HRMS: m/z found [MþNa]þ 413.0959,
C18H18N2O8Na requires 413.0961, m/z: 413 (100%, [MþNa]þ).
Pale yellow solid, mp 125 ꢀC (methanol), 72 mg, 42% yield,
Rf¼0.1 (petroleum ether/EtOAc, 95:5); IR (KBr)/cmꢁ1: 2962 w, 2882
w, 1737 w, 1712 s, 1551 s; 1H NMR (400 MHz, CDCl3): 7.19–7.27 (Ar–
H, m, 5H), 4.04 (Is–CH, d, 1H, J¼8.0 Hz), 3.95 (Ar–CH, d, 1H,
J¼8.0 Hz), 3.43 (CO2CH3, s, 3H), 2.50 (Is–CH3, s, 3H), 2.33 (COCH3, s,
3H); 13C NMR (100.6 MHz): 198.6, 168.9, 166.4, 155.9, 132.5, 131.0,
128.6, 128.5, 128.3, 52.8, 50.3, 36.9, 29.8, 28.5, 11.6; HRMS: m/z
found [MþNa]þ 367.0900, C17H16N2O6Na requires 367.0906, m/z:
367 (100%, [MþNa]þ).
3.3.4. 2-(4-Chloro-phenyl)-3-(3-methyl-4-nitro-isoxazol-5-yl)-
cyclopropane-1,1-dicarboxylic acid dimethyl ester 7d
3.4.3. 2-Methyl-5-(3-methyl-4-nitro-isoxazol-5-yl)-4-p-tolyl-4,5-
dihydrofuran-3-carboxylic acid methyl ester 10b
Yellow oil, 154 mg, 78% yield, Rf¼0.1 (petroleum ether/EtOAc,
75:25); IR (neat)/cmꢁ1: 3001 w, 2954 w, 2865 w, 1749 s, 1560 s; 1H
NMR (400 MHz, CDCl3): 7.21 (Ar–H, m, 5H), 4.14 (Is–CH, d, 1H,
J¼8.0 Hz), 3.82 (Ar–CH, d, 1H, J¼8.0 Hz), 3.66 (CO2CH3, s, 3H), 3.47
(CO2CH3, s, 3H), 2.49 (Is–CH3, s, 3H); 13C NMR (100.6 MHz): 168.21,
166.04, 164.82, 156.04, 134.24, 131.91, 130.67, 129.91, 128.80, 53.56,
53.24, 44.70, 35.56, 26.33, 11.56; HRMS: m/z found [MþNa]þ
417.0454, C17H15ClN2O7Na requires 417.0465, m/z: 417 (100%,
[MþNa]þ).
Yellow solid, 81 mg, 45% yield, Rf¼0.2 (petroleum ether/EtOAc,
95:5); IR (KBr)/cmꢁ1: 2987 w, 2859 w, 1731 s, 1544 s; for trans
isomer: 1H NMR (400 MHz, CDCl3): 7.08 (Ar–H, m, 4H), 5.97 (Is–CH,
d, 1H, J¼4.0 Hz), 4.36 (Ar–CH, m, 1H), 3.51 (CO2CH3, s, 3H), 2.53 (Is–
CH3, s, 3H), 2.37 (CH3–C–O, s, 3H), 2.27 (Ar–CH3, s, 3H); 13C NMR
(100.6 MHz): 170.8, 168.2, 165.0, 156.0, 138.1, 137.5, 130.6, 129.6,
127.0, 107.1, 82.1, 53.8, 51.2, 21.2, 14.0, 11.5; for cis isomer: 1H NMR
(400 MHz, CDCl3): 6.84 (Ar–H, d, 2H, J¼8.0 Hz), 6.76 (Ar–H, d, 2H,
J¼8.0 Hz), 6.37 (Is–CH, d, 1H, J¼10.0 Hz), 4.87 (Ar–CH, dd, 1H,
J1¼10.0 Hz, J2¼1.2 Hz), 3.50 (CO2CH3, s, 3H), 2.41 (Is–CH3, s, 3H),
2.25 (CH3–C–O, s, 3H), 2.13 (Ar–CH3, s, 3H); 13C NMR (100.6 MHz):
170.1, 129.1, 81.5, 52.2, 11.1; HRMS: m/z found [MþNa]þ 381.1053,
C18H18N2O6Na requires 381.1063, m/z: 381 (100%, [MþNa]þ).
3.3.5. 2-(3-Methyl-4-nitro-isoxazol-5-yl)-3-pyridin-2-yl-cyclo-
propane-1,1-dicarboxylic acid dimethyl ester 7e
Yellow oil, 126 mg, 70% yield, Rf¼0.2 (petroleum ether/EtOAc,
75:25); IR (neat)/cmꢁ1: 2990 w, 2985 w, 2880 w, 1740 s, 1544 s;
1H NMR (400 MHz, CDCl3): 8.41 (Py–H, m, 1H), 7.62 (Py–H, m,
1H), 7.38 (Py–H, d, 1H, J¼7.6 Hz), 7.14 (Py–H, m, 1H), 4.22 (Is–CH,
d, 1H, J¼7.6 Hz), 3.75 (Py–CH, d, 1H, J¼7.6 Hz), 3.65 (CO2CH3, s,
3H), 3.57 (CO2CH3, s, 3H), 2.50 (Is–CH3, s, 3H); 13C NMR
(100.6 MHz): 168.4, 166.7, 165.2, 156.0, 152.5, 149.2, 136.7, 130.1,
124.4, 122.8, 53.6, 53.0, 44.4, 36.3, 27.4, 11.7; HRMS: m/z found
[MþHþ] 362.0982, C16H16N3O7 requires 362.0988, m/z: 362
(100%, [MþHþ]).
3.4.4. 1-Acetyl-2-(3-methyl-4-nitro-isoxazol-5-yl)-3-p-tolyl-cyclo-
propanecarboxylic acid methyl ester 11b
Pale yellow solid, mp 115 ꢀC (methanol), 52 mg, 29% yield,
Rf¼0.1 (petroleum ether/EtOAc, 95:5); IR (neat)/cmꢁ1: 2962 w,
2927 w, 2842 w, 1750 s, 1705 s, 1554 s; 1H NMR (400 MHz, CDCl3):
7.17 (Ar–H, m, 4H), 4.10 (Is–CH, d, 1H, J¼8.4 Hz), 4.00 (Ar–CH, d, 1H,
J¼8.4 Hz), 3.55 (CO2CH3, s, 3H), 2.59 (Is–CH3, s, 3H), 2.42 (COCH3, s,
3H), 2.36 (Ar–CH3, s, 3H); 13C NMR (100.6 MHz): 198.7, 169.0, 166.5,
155.9, 138.1, 130.4, 129.3, 128.4, 52.9, 50.3, 36.9, 29.8, 28.5, 21.2, 11.6;
HRMS: m/z found [MþNa]þ 381.1045, C18H18N2O6Na requires
381.1063, m/z: 381 (100%, [MþNa]þ).
3.4. Experimental procedure for the reaction of 2a–f
and methyl acetoacetate 3b
Isoxazoles 2a–f (1 mmol) and methyl acetoacetate 3b (3 mmol)
were taken in THF (10 mL) and added DBU (1 mmol) drop wise at
0 ꢀC. The reaction mixture was stirred at 0 ꢀC for 30 min. Then the
reaction mixture was diluted with EtOAc (20 mL) and washed with
3 N HCl (10 mL), water (20 mL), and brine (10 mL). The organic
phase was separated, dried over anhydrous Na2SO4, filtered, and
3.4.5. 4-(4-Methoxy-phenyl)-2-methyl-5-(3-methyl-4-nitro-
isoxazol-5-yl)-4,5-dihydrofuran-3-carboxylic acid methyl ester 10c
Pale yellow solid, 96 mg, 56% yield, Rf¼0.3 (petroleum ether
/EtOAc, 95:5); IR (KBr)/cmꢁ1: 2977 w, 2858 w, 1717 s, 1549 s; for
trans isomer: 1H NMR (400 MHz, CDCl3): 7.20 (Ar–H, d, 2H,
J¼8.8 Hz), 6.90 (Ar–H, d, 2H, J¼8.8 Hz), 6.05 (Is–CH, d,1H, J¼4.0 Hz),

5408
M.F.A. Adamo et al. / Tetrahedron 65 (2009) 5402–5408
4.44 (Ar–CH, d, 1H, J¼4.0 Hz), 3.82 (Ar–OCH3, s, 3H), 3.60 (CO2CH3,
s, 3H), 2.62 (Is–CH3, s, 3H), 2.46 (CH3–C–O, s, 3H); 13C NMR
(100.6 MHz): 170.8, 168.1, 165.0, 159.1, 156.0, 133.2, 130.4, 128.2,
114.2, 107.2, 82.2, 55.3, 53.5, 51.2, 14.0, 11.5; for cis isomer: 1H NMR
(400 MHz, CDCl3): 7.20 (Ar–H, d, 2H, J¼8.8 Hz), 6.66 (Ar–H, d, 2H,
J¼8.8 Hz), 6.45 (Is–CH, d, 1H, J¼10.4 Hz), 4.96 (Ar–CH, d, 1H,
J¼10.4 Hz), 3.72 (Ar–OCH3, s, 3H), 3.59 (CO2CH3, s, 3H), 2.50 (Is–
CH3, s, 3H), 2.35 (CH3–C–O, s, 3H); HRMS: m/z found [MþNa]þ
397.1017, C18H18N2O7Na requires 397.1012, m/z: 397 (100%,
[MþNa]þ).
2854 w, 1719 s, 1546 s; 1H NMR (400 MHz, CDCl3): 6.87 (Thiop–H,
d, 1H, J¼3.6 Hz), 6.71 (Thiop–H, dd, 1H, J1¼3.6 Hz, J2¼0.4 Hz), 6.01
(Is–CH, d, 1H, J¼3.2 Hz), 4.59 (Thiop–CH, m, 1H), 3.59 (CO2CH3, s,
3H), 2.54 (Is–CH3, s, 3H), 2.37 (CH3–C–O, s, 3H); 13C NMR
(100.6 MHz): 170.1, 169.4, 164.5, 156.1, 145.9, 130.6, 130.1, 125.5,
111.6, 106.1, 81.9, 51.4, 49.9, 14.1, 11.4. Anal. Calcd for
C15H13BrN2O6S: C 41.97%, H 3.05%, N 6.53%. Found: C 42.19%, H
3.19%, N 6.39%.
3.4.11. 1-Acetyl-2-(5-bromothiophen-2-yl)-3-(3-methyl-4-nitro-
isoxazol-5-yl)-cyclopropanecarboxylic acid methyl ester 11f
Yellow solid mp 114–116 ꢀC (methanol), 21 mg, 10% yield,
Rf¼0.2, (petroleum ether/EtOAc, 90:10); IR (neat)/cmꢁ1: 3020 w,
2869 w, 1741 s, 1715 s, 1553 s; 1H NMR (400 MHz, CDCl3): 6.85
(Thiop–H, d, 1H, J¼3.6 Hz), 6.68 (Thiop–H, d, 1H, J¼3.6 Hz), 3.92
(Is–CH, d, 1H, J¼8.0 Hz), 3.87 (Thiop–CH, d, 1H, J¼8.0 Hz), 3.64
(CO2CH3, s, 3H), 2.50 (Is–CH3, s, 3H), 2.33 (COCH3, s, 3H); 13C NMR
(100.6 MHz): 197.9, 167.8, 166.0, 156.0, 136.7, 130.6, 129.9, 127.9,
112.5, 53.4, 50.4, 31.7, 29.8, 29.7, 11.6. Anal. Calcd for
C15H13BrN2O6S: C 41.97%, H 3.05%, N 6.53%. Found: C 42.12%, H
3.21%, N 6.29%.
3.4.6. 1-Acetyl-2-(4-methoxy-phenyl)-3-(3-methyl-4-nitro-isoxazol-
5-yl)-cyclopropanecarboxylic acid methyl ester 11c
Yellow oil, 60 mg, 35% yield, Rf¼0.2 (petroleum ether/EtOAc,
95:5); IR (neat)/cmꢁ1: 2986 w, 2883 w, 1747 s, 1710 s, 1560 s; 1H
NMR (400 MHz, CDCl3): 7.12 (Ar–H, d, 2H, J¼8.4 Hz), 6.79 (Ar–H, d,
2H, J¼8.4 Hz), 3.99 (Is–CH, d, 1H, J¼8.4 Hz), 3.91 (Ar–CH, d, 1H,
J¼8.4 Hz), 3.73 (Ar–OCH3, s, 3H), 3.47 (CO2CH3, s, 3H), 2.50 (Is–CH3,
s, 3H), 2.33 (COCH3, s, 3H); 13C NMR (100.6 MHz): 198.8, 169.0,
166.5, 159.5, 155.9, 130.2, 129.7, 124.3, 114.0, 55.3, 52.9, 50.4, 36.7,
29.8, 28.7, 11.6; HRMS: m/z found [MþNa]þ 397.1016, C18H18N2O7Na
requires 397.1012, m/z: 397 (100%, [MþNa]þ).
Acknowledgements
3.4.7. 4-(4-Chloro-phenyl)-2-methyl-5-(3-methyl-4-nitro-isoxazol-
5-yl)-4,5-dihydrofuran-3-carboxylic acid methyl ester 10d
We acknowledge the PTRLI cycle III for a grant to MFAA, the
Health Research Board (HRB) for financial support to S.S., and SFI
RFP2006 for financial support to L.P.
Pale yellow solid, 69 mg, 40%, Rf¼0.3 (petroleum ether/EtOAc,
95:5); IR (KBr)/cmꢁ1: 2998 w, 2838 w, 1730 s, 1550 s; for trans
isomer: 1H NMR (400 MHz, CDCl3): 7.25 (Ar–H, d, 2H, J¼8.4), 7.13
(Ar–H, d, 2H, J¼8.4 Hz), 5.95 (Is–CH, d, 1H, J¼4.0 Hz), 4.36 (Ar–CH,
m, 1H), 3.51 (CO2CH3, s, 3H), 2.53 (Is–CH3, s, 3H), 2.38 (CH3–C–O, s,
3H); 13C NMR (100.6 MHz): 170.5, 168.6, 164.7, 156.0, 139.6, 133.6,
130.6, 129.1,128.6,106.9, 81.9, 53.7, 51.3,14.0,11.5; for cis isomer: 1H
NMR (400 MHz, CDCl3):7.03 (Ar–H, d, 2H, J¼8.4 Hz), 6.84 (Ar–H, d,
2H, J¼8.4 Hz), 6.38 (Is–CH, d, 1H, J¼10.4 Hz), 4.89 (Ar–CH, d, 1H,
J¼10.4 Hz), 3.50 (CO2CH3, s, 3H), 2.41 (Is–CH3, s, 3H), 2.28 (CH3–C–
O, s, 3H); HRMS: m/z found [MþNa]þ 401.0526, C17H15ClN2O6Na
requires 401.0516, m/z: 401 (100%, [MþNa]þ).
References and notes
1. (a) Adamo, M. F. A.; Chimichi, S.; De Sio, F.; Donati, D.; Sarti-Fantoni, P. Tetra-
hedron Lett. 2002, 43, 4157; (b) Adamo, M. F. A.; Donati, D.; Duffy, E. F.; Sarti-
Fantoni, P. J. Org. Chem. 2005, 70, 8395.
2. Adamo, M. F. A.; Duffy, E. F. Org. Lett. 2006, 8, 5157.
3. Adamo, M. F. A.; Konda, V. R. Org. Lett. 2007, 9, 303.
4. Adamo, M. F. A.; Duffy, E. F.; Konda, V. R.; Murphy, F. Heterocycles 2007, 71, 1173
and references cited therein.
5. Adamo, M. F. A.; Duffy, E. F.; Donati, D.; Sarti-Fantoni, P. Tetrahedron 2007, 63,
2047.
6. Adamo, M. F. A.; Duffy, E. F.; Donati, D.; Sarti-Fantoni, P. Tetrahedron 2007, 63,
2684.
7. Adamo, M. F. A.; Nagabelli, M. Tetrahedron Lett. 2007, 48, 4703.
8. Adamo, M. F. A.; Konda, V. R.; Donati, D.; Sarti-Fantoni, P.; Torroba, T. Tetrahe-
dron 2007, 63, 9741.
9. Adamo, M. F. A.; Konda, V. R. Tetrahedron Lett. 2008, 49, 6224.
10. Adamo, M. F. A.; Bruschi, S.; Suresh, S.; Piras, L. Tetrahedron Lett. 2008, 49,
7406.
11. Sarti-Fantoni, P.; Donati, D.; De Sio, F.; Moneti, G. J. Heterocycl. Chem. 1980, 17,
1643; Baracchi, A.; Chimichi, S.; De Sio, F.; Donati, D.; Nesi, R.; Sarti-Fantoni, P.;
Torroba, T. J. Labelled Compd. Radiopharm. 1986, 23, 487.
12. (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009; (b) Yin, L.;
Liebscher, J. Chem. Rev. 2007, 107, 133.
13. Barbero, A.; Pulido, F. J. Synthesis 2004, 401.
14. (a) Churykau, D. H.; Zinovich, V. G.; Kulinkovich, O. G. Synlett 2004, 1949; (b)
Bode, J. W.; Carreira, E. M. Org. Lett. 2001, 3, 1587.
15. Li, C. S.; Lacasse, E. Tetrahedron Lett. 2002, 43, 3565.
16. (a) Nitta, M.; Kobayashi, T. J. Chem. Soc., Chem. Commun. 1982, 877; (b) Baraldi,
P. G.; Barco, A.; Benetti, S.; Guarneri, M.; Manfredini, S.; Pillini, G. P.; Simoni, D.
Tetrahedron Lett. 1985, 26, 5319.
17. Auricchio, S.; Bini, A.; Pastormerlo, E.; Truscello, A. M. Tetrahedron 1997, 53.
18. (a) Nesi, R.; Turchi, S.; Giomi, D. J. Org. Chem. 1996, 61, 7933; (b) Nesi, R.; Giomi,
D.; Turchi, S. J. Org. Chem. 1998, 63, 6050.
19. Adamo, M. F. A.; Nagabelli, M. Org. Lett. 2008, 10, 1807.
20. Baracchi, A.; Chimichi, S.; De Sio, F.; Donati, D.; Nesi, R.; Sarti-Fantoni, P.; Tor-
roba, T. J. Labelled Compd. Radiopharm. 1986, 23, 487.
21. Data deposited at the Cambridge Crystallographic Data Centre, CCDC 715687.
22. (a) Hamelin, J.; Saoudi, A.; Benhaoua, H. Synthesis 2003, 2185; (b) Concelln, J.
M.; Huerta, M. J. Org. Chem. 2005, 70, 4714; (c) Shishido, Y.; Ito, F.; Morita, H.;
Ikunaka, M. Bioorg. Med. Chem. Lett. 2007, 17, 6887.
23. Data deposited at the Cambridge Crystallographic Data Centre, CCDC
715688.
24. Data deposited at the Cambridge Crystallographic Data Centre, CCDC
715689.
3.4.8. 1-Acetyl-2-(4-chloro-phenyl)-3-(3-methyl-4-nitro-isoxazol-
5-yl)-cyclopropanecarboxylic acid methyl ester 11d
Yellow oil, 61 mg, 36% yield, Rf¼0.1 (petroleum ether/EtOAc,
95:5); IR (neat)/cmꢁ1: 2995 w, 2882 w,1739 s,1705 s,1559 s; 1H NMR
(400 MHz, CDCl3): 7.25 (Ar–H, d, 2H, J¼8.4 Hz), 7.15 (Ar–H, d, 2H,
J¼8.4 Hz), 4.00 (Is–CH, d,1H, J¼8.4 Hz), 3.90 (Ar–CH, d,1H, J¼8.4 Hz),
3.84 (CO2CH3, s, 3H), 2.32 (Is–CH3, s, 3H); 13C NMR (100.6 MHz):
198.3, 168.4, 166.2, 155.9, 134.3, 131.0, 130.2, 128.8, 81.9, 53.0, 50.2,
36.0, 28.5, 11.6; HRMS: m/z found [MþNa]þ 401.0522,
C17H15ClN2O6Na requires 401.0516, m/z: 401 (100%, [MþNa]þ).
3.4.9. 1-Acetyl-2-(3-methyl-4-nitro-isoxazol-5-yl)-3-pyridin-2-yl-
cyclopropanecarboxylic acid methyl ester 11e
Yellow oil, 87 mg, 50% yield, Rf¼0.2 (petroleum ether/EtOAc,
95:5); IR (neat)/cmꢁ1: 2992 w, 2877 w, 1750 s, 1720 s, 1558 s; 1H
NMR (400 MHz, CDCl3): 8.41 (Py–H, m, 1H), 7.31 (Py–H, m, 1H), 7.35
(Py–H, d, 1H, J¼7.6 Hz), 7.14 (Py–H, m, 1H), 4.12 (Is–CH, d, 1H,
J¼7.6 Hz), 3.77 (Py–CH, d, 1H, J¼7.6 Hz), 3.61 (CO2CH3, s, 3H), 2.49
(Is–CH3, s, 3H), 2.30 (COCH3, s, 3H); 13C NMR (100.6 MHz): 198.6,
167.1, 155.8, 152.9, 149.2, 136.7, 130.9, 124.5, 122.8, 53.0, 37.3, 29.4,
29.3, 14.1, 11.6; HRMS: m/z found [MþH]þ 346.1037, C16H16N3O6
requires 346.1039, m/z: 346 (100%, [MþH]þ).
3.4.10. 4-(5-Bromothiophen-2-yl)-2-methyl-5-(3-methyl-4-nitro-
isoxazol-5-yl)-4,5-dihydrofuran-3-carboxylic acid methyl ester 10f
Yellow solid, mp 129–130 ꢀC (ethanol), 21 mg, 10% yield,
Rf¼0.2 (petroleum ether/EtOAc, 90:10); IR (KBr)/cmꢁ1: 3001 w,
25. Data deposited at the Cambridge Crystallographic Data Centre, CCDC
715690.