Michael additions versus cycloaddition condensations with ethyl nitroacetate and electron-deficient olefins

Article abstract of DOI:10.1002/chem.200802652

Ethyl nitroacetate (1) reacts with electron-poor olefins in the presence of a base to give either the Michael adducts 3 or the isoxazoline cycloadducts 4, resulting from water elimination. The proportions of the two products depend on the reaction conditi

Full text of DOI:10.1002/chem.200802652

DOI: 10.1002/chem.200802652
Michael Additions versus Cycloaddition Condensations with
Ethyl Nitroacetate and Electron-Deficient Olefins
Elena Trogu,[a] Francesco De Sarlo,*[a] and Fabrizio Machetti*[b]
Dedicated to the Centenary of the Italian Chemical Society
Abstract: Ethyl nitroacetate (1) reacts
reactions show that the cycloaddition-
condensations require long induction
times that dramatically decrease upon
addition of a copper salt to the catalyt-
ic system: the drops in the induction
time cause increases in the proportion
with electron-poor olefins in the pres-
ence of a base to give either the Mi-
chael adducts 3 or the isoxazoline cy-
cloadducts 4, resulting from water
elimination. The proportions of the
two products depend on the reaction
conditions and change in the course of
the process. Kinetic profiles for the two
of cycloadducts 4, which are often the
sole reaction products. This is the first
report on the selective formation of
products 3 and 4 from primary nitro
compounds through modulation of the
catalytic system.
Keywords: copper · cycloaddition ·
Michael addition · nitro compounds
Introduction
base if the electron-poor olefin is very reactive, such as
methyl vinyl ketone.[31,32]
Anions derived from base treatment of nitro compounds are
known to undergo conjugate additions with electron-poor
olefins.[1] These (Michael-type[2,3]) reactions [Eq. (1)] have
been widely explored and exploited for many polyfunctional
targets.[4–10] Strong bases such as tetramethylguanidine
(TMG),[11,12] DBU,[13–18] benzyltrimethylammonium hydrox-
ide (Triton B[19–21]) or NaOH[22] are usually required to gen-
erate the nucleophilic species. However, “activated” nitro
compounds [Eq. (1), R1 =EWG] are strong enough to un-
dergo the reactions with catalysis by bases of moderate
strength[23] (triethylamine,[24–28] PPh3[29,30]) or even without a
Primary nitro compounds are shown here also to undergo,
in competition with conjugate additions, cycloaddition-con-
densation processes involving their nitro groups and leading
to isoxazole derivatives [Eq. (2)].[33] In fact, we have recent-
ly reported that cycloaddition-condensations between acti-
vated primary nitro compounds and alkenes or alkynes take
place under base catalysis conditions, with the best results
being obtained with bases that possess two basic centres and
are best-suited for H-bonding (e.g. 1,4-diazabicyclo-
[a] Dr. E. Trogu, Prof. F. De Sarlo
Dipartimento di Chimica Organica ꢀU. Schiff’
Universitꢁ di Firenze, Via della Lastruccia 13
50019 Sesto Fiorentino, Firenze (Italy)
Fax : (+39)0554573531
E-mail: fdesarlo@unifi.it
[b] Prof. Dr. F. Machetti
AHCTUNGTRENNUNG
Istituto di Chimica dei Composti Organometallici
del Consiglio Nazionale delle Ricerche
c/o Dipartimento di Chimica Organica ꢀU. Schiff’
Universitꢁ di Firenze, Via della Lastruccia 13
50019 Sesto Fiorentino, Firenze (Italy)
Fax : (+39)0554573531
are expected to react with the anion of an activated primary
nitro compound according to either [Eq. (1)] or [Eq. (2)].
The conditions affecting the competition between these
two processes are considered and discussed here, in order to
E-mail: fabrizio.machetti@unifi.it
7940
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Chem. Eur. J. 2009, 15, 7940 – 7948

FULL PAPER
Table 1. Effect of temperature and base on the ratios between Michael adducts 3 and cycloadducts 4.[a]
establish how catalyst and re-
action conditions could favour
one result or the other.
Results and Discussion
Base[b]
T [8C]
t [h]
Conv. [%][c]
Yield 3 [%][d]
Yield 4 [%][d]
Under
base
catalysis
Entry
2
(DABCO) conditions, ethyl ni-
troacetate (1, Table 1), regard-
ed as a model “activated” nitro
compound,[37,38] reacts with
compounds 2, containing elec-
tron-deficient double bonds, in
two ways, to give either the
Michael-type open-chain ad-
ducts 3 or the cycloadducts 4
as a result of water elimina-
tion.
The results reported in
Table 1 show strong depend-
ence on the dipolarophile and
on the reaction conditions.
Condensation appears to be
favoured over conjugate addi-
tion as the temperature in-
creases (cf. entries 1 and 2, 5
and 6, 9 and 10, 13 and 14).
Attempted use of other bases
1
2
3
4
5
6
7
8
a[e]
a
a
DABCO
DABCO
NMP
30
60
60
60
30
60
60
60
30
60
60
60
30
60
60
60
60
60
240
48
168
88
240
48
120
168
240
168
120
18
96
20
96
18
18
18
88
88
59
47
79
24
18
13
38
64
41
30
91
90
80
58
82
88
97
0
100
100
79
10
100
69
39
100
86
41
52
0
b
DBU
b[e]
b
DABCO
DABCO
NMP
DIPEA
DABCO
DABCO
NMP
0
82
55
0
36
36
37
0
b
b
c
c
9
10
11
12
13
14
15
16
17
18
c
67
c[e]
d[e]
d
DBU
100
100
100
87
100
100
100
DABCO
DABCO
NMP
NMP
NMI
0
19
29
0
11
0
d
e[e]
e
e
DABCO
[a] See Experimental Section for details. [b] DABCO: 1,4-diazabicyclo
dine. DBU: 1,8-diazabicyclo
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
[c] Degree of conversion based on the consumption of dipolarophile and determined by 1H NMR spectrosco-
py. [d] Spectroscopic yield determined by 1H NMR with use of an internal standard. [e] Compound 3 was iso-
lated and characterised; see Experimental Section.
indicates that a very strong base such as DBU greatly fa-
vours products 3 over 4 (cf. entries 4 and 6), whereas
DABCO ensures faster conversions with variable propor-
tions of products: moreover, the molar ratio between, for
example, 3a and 4a changes as the reaction proceeds. How-
ever, we have verified that compounds 3 and 4 do not inter-
convert into one another under the reaction conditions, so
the ratio between them does not depend on kinetic vs. ther-
modynamic control.
concentrations of the dipolarophile 2a and of the products
3a and 4a are plotted versus time at different base concen-
trations in Figure 1. The formation of the cycloadduct 4a ex-
hibits a long induction period, as in the case of the previous-
ly reported reaction between ethyl nitroacetate and sty-
rene,[39] thus suggesting a common mechanism for the two
reactions: a reversible cycloaddition of the nitronate to the
dipolarophile precedes the rate-determining step, in which
irreversible water release leads to the product 4a
(Scheme 1, path A). Indeed, it would be hard to explain why
cycloadduct (4) should be favoured with respect to open-
chain Michael adduct (3) as the temperature increases
(Table 1) were cycloaddition the rate-determining step. The
conjugate addition (Scheme 1, path B) takes place without
any significant induction time, and its initial rate can be ap-
proximately evaluated from the graphs (Figure 1), because
during early reaction stages the condensation rate can be
neglected. The reaction is first order in the base, as would
be expected,[40] so the cycloaddition-condensation to afford
4a becomes predominant at low base concentrations
(Figure 1, bottom), because the induction time is apparently
barely affected. However, the conversion requires exceed-
ingly long times to go to completion.
The model reaction between ethyl nitroacetate (1) and
methyl acrylate (2a) was monitored by 1H NMR. Molar
Abstract in Italian: Il nitroacetato di etile (1) reagisce con
olefine elettron-povere, in presenza di base, per dare sia l’ad-
dotto di Michael (3) che, con eliminazione di acqua, il ci-
cloaddotto isossazolinico (4). Il rapporto tra i prodotti 3 e 4
cambia nel corso del processo e dipende dalle condizioni di
reazione. I profili cinetici delle due reazioni mostrano che la
cicloaddizione-condensazione ꢀ caratterizzata da un tempo
di induzione il cui valore diminuisce notevolmente all’aggiun-
ta nel sistema catalitico di sali di rame(II): la diminuzione del
tempo di induzione provoca un incremento della quantitꢁ di
cicloaddotto 4 che spesso ꢀ l’unico prodotto. Questo lavoro
rappresenta il primo esempio di trasformazione selettiva di
nitrocomposti primari nei prodotti 3 o 4 attraverso la modu-
lazione del sistema catalitico.
We have recently reported that, in the presence of a base,
addition of catalytic amounts of a CuII salt allows various di-
polarophiles to undergo the cycloaddition-condensation not
only with activated nitro compounds, but also with nitroal-
kanes.[39,41] Surprisingly, under these conditions, nitroalkanes
Chem. Eur. J. 2009, 15, 7940 – 7948
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7941

F. Machetti, F. De Sarlo, and E. Trogu
Scheme 1. Competition between conjugate addition (path B, curly
arrows) and cycloaddition-condensation (path A, dotted interaction) in
the model reaction between ethyl nitroacetate and methyl acrylate.
obtained from phenyl vinyl sulfone (2d) and methyl vinyl
ketone (2e), whereas in other reactions minor amounts of
adducts 3 could be observed only at 308C (Table 2, entries 1,
8).
The effect of the temperature on product ratios thus fol-
lows the same trend as observed in the reactions in the ab-
sence of copper(II) (Table 1). In reactions of methyl vinyl
ketone (2e) the ratio between the products 3e and 4e de-
pends on the base employed (Table 2, entries 14–19), but we
were unable to achieve a high selectivity towards 4e. Kinetic
profiles for the reaction 1+2a [2a (1 equiv), DABCO
(0.1 equiv), CuACTHNUTRGNEUNG(OAc)2 (0.05 equiv), in chloroform at 608C]
are illustrated in Figure 2 (plots a–d). The presence of an
excess of nitroacetate (1, in the range from 2.5 to 1 equiv)
affects the reaction course as shown in Figure 2: after 24 h
the degree of conversion is over 90% even without an
excess of nitroacetate, whereas above 1.5 equivalent conver-
sion is quantitative after 12 h.
The presence of CuII thus causes a dramatic drop in the
induction times, whereas the maximum rate appears to be
scarcely affected. In fact, the maximum reaction rates as
evaluated from the graphs in Figure 2 (9 to 14ꢃ
10À6 moldmÀ3 sÀ1) and the graph in Figure 1 (top) (6ꢃ
10À6 moldmÀ3 sÀ1) are not very different, the gap possibly
arising from the difference in dipolarophile concentrations.
These observations suggest that the copper salt has a cata-
lytic effect mainly on the cycloaddition pre-equilibrium,
whereas only a minor effect (if any) on the rate-determining
dehydration step is observed.
Figure 1. Kinetic profiles for reactions between ethyl nitroacetate (1) and
methyl acrylate (2a) in the presence of DABCO at 2a/DABCO molar
ratios of 1:0.1 (top), 1:0.075 (middle) and 1:0.05 (bottom). Plots of 2a
~
(*), 3a (*) and 4a ( ) concentrations versus time. The reactions were
each performed in a septum-sealed NMR tube in the probe of the spec-
trometer at 608C. See Experimental Section for details.
also give excellent yields of the corresponding isoxazolines
with methyl acrylate, among other substrates. Therefore, the
reactions considered so far (Table 1) were repeated in the
presence of a CuII salt. Addition of a copper salt to the cata-
lytic system dramatically increased the proportions of cyclo-
adducts 4, which were often the sole reaction product
(Table 2). Significant amounts of open-chain adducts 3 were
Synthetic opportunities: The scope of the reactions of ethyl
nitroacetate (1) has been extended to mono- and polysubsti-
tuted electron-poor dipolarophiles, with employment of the
most favourable conditions leading to isoxazole derivatives.
The reaction with methyl acrylate (2a), as we have seen
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Chem. Eur. J. 2009, 15, 7940 – 7948

Michael Additions versus Cycloaddition Condensations
FULL PAPER
Table 2. Effect of copper(II) acetate on the ratios between Michael adducts 3a–e and cycloadducts 4a–e.[a]
(NMM) was preferred in the
case of methyl vinyl ketone
(2e; see entry 15 in Table 2).
With the copper/base cata-
lytic system in chloroform at
608C, the cyclic dehydrated ad-
ducts 4 were the main prod-
ucts. Significant amounts of the
regioisomeric cycloadduct (5g)
were only obtained from the
reaction with methyl crotonate
(2g).[42] Other by-products ob-
tained in addition to 4 were:
the conjugate adduct 3e, ob-
served in the reaction with
methyl vinyl ketone (2e), and
the aromatised isoxazole 6,
from reactions either with di-
methyl maleate (2h) or with
dimethyl fumarate (2i). It is
worth noting that the cycload-
dition-condensation was faster
with dimethyl maleate (2h)
than with dimethyl fumarate
(2i) and that these substrates
in fact gave the same mixtures
of the diastereoisomers 4h (cis,
less than 10%) and 4i (trans).
These isoxazolines were both
dehydrogenated to 6 under the
reaction conditions;[43] in fact
Entry
2
Base[b]
T [8C]
t [h]
Conv. [%][c]
Yield 3 [%][d]
Yield 4 [%][d]
1
2
3
4
5
6
7
8
a
a
a
b
b
b
b
c
DABCO
DABCO
NMP
DABCO
DABCO
NMP
DIPEA
DABCO
DABCO
NMP
DABCO
DABCO
NMP
DABCO
NMM
NMI
imidazole
DMP
NPyM
30
60
60
30
60
60
60
30
60
60
30
60
60
60
60
60
60
60
60
240
20
20
240
20
20
66
168
20
20
144
20
20
18
18
18
18
18
18
100
100
100
100
100
100
100
57
100
100
75
100
94
100
100
100
100
100
100
24
0
0
0
0
0
0
17
0
0
26
16
25
75
28
50
73
53
79
74
98
94
98
100
100
100
38
94
97
48
82
55
18
70
47
27
47
14
9
c
c
10
11
12
13
14
15
16
17
18
19
d
d
d
e
e
e
e
e
e
[a] See Experimental Section for details. [b] NMM: N-methylmorpholine. DMP: 1,4-dimethylpiperazine.
NPyM: N-(4-pyridinyl)morpholine. [c] Degree of conversion based on the consumption of dipolarophile and
determined by 1H NMR spectroscopy. [d] Spectroscopic yield determined by 1H NMR with use of an internal
standard.
the observed amount of isoxazole 6 was higher in the reac-
tion with dimethyl fumarate (2i) because that reaction took
Table 3. 4,5-Dihydroisoxazoles from ethyl nitroacetate (1) and olefins
2a–j.[a]
Figure 2. Kinetic profiles for condensations between ethyl nitroacetate
(1) and methyl acrylate (2a) at different 1/2a molar ratios: 2.5:1,
plot a (*); 1.5:1, plot b (*); 1.2:1, plot c (&); 1:1, plot d (&). The reac-
tions were performed in septum-sealed NMR tubes in the probe of the
spectrometer at 608C. See Experimental Section for details.
Entry
2
X
Y
Z
Products[b]
Yield [%][c]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
CO2Me
CONMe2
CN
SO2Ph
COMe
CO2Me
CO2Me
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
Me
4a
4b
4c
4d
89
100
85
83
90
93
76
A
(Figure 2), is conveniently carried out with 1.5 equivalents
of ethyl nitroacetate (1). These conditions represent the
right balance between conversion, reaction time and nitroa-
cetate consumption. The same ratio was applied to most of
the reactions reported in Table 3 (entries 1–7), whereas
larger excesses of 1 (2.5 equiv) were required for the less re-
active substrates (entries 8–10). N-Methylpiperidine (NMP)
was employed as a base, except that N-methylmorpholine
4 f
(4g+5g)[e]
CO2Me CO2Me
CO2Me
-CO-N(Ph)-CO-
ACHTUNGTRENNUNG
9
10
CO2Me
H
H
ACHTUNGTRENNUNG
j
4j
71
[a] See Experimental Section for more details. [b] Products in parenthesis
are not separated. [c] Isolated yield. [d] 4e/3e 2.5:1 molar ratio. [e] 4g/5g
1.8:1 molar ratio. [f] 4h/4i 1:10 molar ratio [g] (4h+4i)/6 11:1 molar
ratio. [h] (4h+4i)/6 1:2 molar ratio.
Chem. Eur. J. 2009, 15, 7940 – 7948
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7943

F. Machetti, F. De Sarlo, and E. Trogu
with Autonom (Beilstein Information Systems) and modified where ap-
propriate.
longer. The data in Table 3 refer to reactions set up for the
highest selectivities in favour of isoxazole derivatives 4. On
the other hand, previous literature data and the results re-
ported here indicate that factors enhancing selectivity in
favour of conjugate addition are: i) absence of CuII catalyst,
ii) use of strong bases such as DBU (cf. entries 4 and 6 in
Table 1), iii) increased base concentration (cf. Figure 1), and
iv) increased excess of nitroacetate, as evidenced in the reac-
tion with phenyl vinyl sulfone (2d). Thus, a large excess
(2.5 equiv of nitroacetate 1 with respect to olefin 2d) gave a
3d/4d ratio of 25:55 (entry 13, Table 2), whereas 1.5 equiv
of 1, under the same conditions, afforded 4d as the sole
product in 83% yield (entry 4, Table 3). However, a detailed
preparative study of the conjugate adducts 3 was not one of
the aims of this research.
Materials: Commercially available (Lancaster and Aldrich) ethyl nitroa-
cetate (1), organic bases and olefins 2a–j were used as supplied. CHCl3
(ethanol-free) was filtered through a short pad of potassium carbonate
just before use.
Effect of temperature and base on the ratios between Michael adducts 3
and cycloadducts 4: The conversions and spectroscopic yields reported in
Table 1 refer to reactions performed in an apparatus in which eight reac-
tions were carried out simultaneously. A mixture of ethyl nitroacetate (1,
1.06 mmol), base (0.0424 mmol) and olefin (0.424 mmol) in chloroform
(1.4 mL) was kept at 308C or 608C. After the indicated time, a portion
was withdrawn from the reaction mixture and diluted with CDCl3
(0.6 mL), and the 1H NMR spectrum was registered. Integration of the
more reliable signals for 2, 3 and 4 gave the conversion ratio. Compounds
3 and 4 were assumed to be the only products to originate from dipolaro-
philes 2. The reaction solution, combined with the NMR sample, was
concentrated in vacuo, and 2’,4’-dimethoxyacetophenone (30–50 mg,
0.18–0.30 mmol) was then added as an internal standard. A portion was
withdrawn and dissolved in CDCl3 (0.6 mL), and the 1H NMR spectrum
was registered. Integration of the 3’- and 5’-proton signals of the internal
standard (m, 6.40–6.58), the signals of the 5-H protons of compounds 4
and the more reliable signals of compounds 3 gave the spectroscopic
yields. In case of an unclear result, a duplicate experiment was run.
Conclusions
This work shows for the first time that the reactions be-
tween a primary nitro compound and electron-deficient ole-
fins can be modulated by use of different conditions and cat-
alytic systems (bases of various strength, presence of CuII
salt) to cause either the well known conjugate additions
(Michael reactions) or cycloaddition-condensations to afford
isoxazole derivatives with involvement of the nitro groups.
The conjugate additions in most cases require strong bases,
whereas with weaker bases the cycloaddition-condensations
might be faster but take place after long induction times;
addition of CuII greatly reduces induction times, thus favour-
ing the cycloaddition-condensations.
Effect of copper(II)acetate on the ratios between Michael adducts and
cycloadducts (Table 2): The conversions and spectroscopic yields report-
ed in Table 2 refer to reactions performed in an apparatus in which eight
reactions were carried out simultaneously. A mixture of ethyl nitroace-
tate (1, 1.06 mmol), base (0.0424 mmol), copper(II) acetate
(0.0212 mmol) and olefin (0.424 mmol) in chloroform (1.4 mL) was kept
at 308C or 608C. After the indicated time, a portion was withdrawn from
the reaction mixture and diluted with CDCl3 (0.6 mL), and the 1H NMR
spectrum was registered. Integration of the more reliable signals for 2, 3
and 4 gave the conversion ratio. Compounds 3 and 4 were assumed to be
the only products to originate from dipolarophiles 2. The reaction solu-
tion, combined with the NMR sample, was concentrated in vacuo, and
2’,4’-dimethoxyacetophenone (30–50 mg, 0.18–0.30 mmol) was then
added as an internal standard. A portion was withdrawn and dissolved in
CDCl3 (0.6 mL), and the 1H NMR spectrum was registered. Integration
of the 3’- and 5’-proton signals of the internal standard (m, 6.40–6.58),
the signals of the 5-H protons of compounds 4 and the more reliable sig-
nals of compounds 3 gave the spectroscopic yields. In case of an unclear
result, a duplicate experiment was run.
Experimental Section
General methods: Melting points were determined in capillaries with a
Bꢄchi 510 apparatus and are uncorrected. Chromatographic separations
were performed on silica gel 60 (40–6.3 mm) with analytical grade sol-
vents, driven by a positive pressure of air; Rf values refer to TLC (visual-
ised with UV light and/or by dipping the plates into a solution of per-
manganate or anisaldehyde followed by heating with a heat gun) carried
out on alumina-backed plates coated with 25 mm silica gel (Merck F254),
with the same eluent as indicated for the column chromatography. For
gradient column chromatography, Rf values refer to the more polar
eluent. Solvent removal was performed by evaporation on a rotary evap-
orator at room temperature. 1H and 13C NMR spectra were recorded
with a Varian Mercuryplus 400 spectrometer (operating at 400 MHz for
1H and 100.58 MHz for 13C) unless otherwise stated. The 1H NMR data
are reported as s=singlet, d=doublet, t=triplet, m=multiplet or unre-
solved, br=broad signal, coupling constant(s) in Hz, integration. Multi-
plicities of the 13C NMR signals and assignments were determined by
means of gHMQC and gHMBC experiments. Chemical shifts were deter-
mined relative to the residual solvent peak (CHCl3: 7.24 ppm for
1H NMR and 77.0 ppm for 13C NMR). EI (electron impact) mass spectra
were obtained with a Shimadzu QP5050 A quadrupole-based mass spec-
trometer (direct introduction unless otherwise stated, at an ionising volt-
age of 70 eV). Ion mass/charge (m/z) ratios are reported as values in
atomic mass units followed by their intensities relative to the base peak
in parentheses; IR spectra were recorded with a Perkin–Elmer 881 spec-
Effect of DABCO concentration on the reaction products from ethyl ni-
troacetate and methyl acrylate (Figure 1): Reactions were run in
a
septum-sealed 5 mm NMR tube spinning (20 Hz) in the probe of the
spectrometer at 608C. Three different molar ratios between DABCO and
methyl acrylate (2a), (0.1, 0.075, 0.05) were screened with changes in the
molar amounts of DABCO.
Preparation of samples: Mother reaction mixtures (kept at À108C in a
freezer until used) were prepared by dissolving DABCO [run a) 9.6 mg;
run b) 7.2 mg; run c) 4.8 mg], ethyl nitroacetate (1, 282 mg), methyl acry-
late (2a, 73 mg) and the internal standard (CH3)2SO2 (20 mg) in CDCl3
(4.04 g, freshly filtered through K2CO3). A sample reaction was obtained
after transfer of 560 mL of the above solutions into a septum-sealed
NMR tube. In cases of unclear results a duplicate reaction was run.
Concentration evaluation: An array of 1H NMR spectra, recorded at in-
tervals of 30 min until no further spectral changes were observed, was
collected for every run, and the concentrations were evaluated by inte-
gration of the CH3 proton signals (2.89 ppm) of the internal standard and
the OCH3 proton signals for 3a and 4a (3.70 and 3.79 ppm, respectively).
Determination of kinetic profiles for different molar ratios between ethyl
nitroacetate (1) and methyl acrylate (2a) (Figure 2): Reactions were run
in a septum-sealed 5 mm NMR tube spinning (20 Hz) in the probe of the
spectrometer at 608C. Four different molar ratios between ethyl nitroace-
tate (1) and methyl acrylate (2a), in the 2.5:1 to 1:1 range, were screened
with changes in the molar amounts of ethyl nitroacetate (1).
trophotometer. Elemental analyses were obtained with
a Perkin–
Elmer 240C Elemental Analyser apparatus. All compounds were named
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Michael Additions versus Cycloaddition Condensations
FULL PAPER
ꢀ
Preparation of reaction samples: Mother reaction mixtures were prepared
by dissolving ethyl nitroacetate (1) [run a) 282 mg; run b) 170 mg; run
c) 136 mg; run d) 113 mg] and DABCO (9.6 mg) in CDCl3 (4.04 g, freshly
filtered through K2CO3). An aliquot portion (1:4) of each mother solu-
tion was weighed[44] [run a) 1.082 g; run b) 1.056 g; run c) 1.047 g; run d)
CH3CH2O), 2.52–2.64 (m, 4H; CH2CH and CH2C N), 4.33 (q, J=8.0 Hz,
2H; CH3CH2O), 5.23–5.27 ppm (m, 1H; CHNO2); 13C NMR: d=13.8 (q;
ꢀ
CH3CH2), 14.0 (t; CH2C N), 26.1 (t; CH2), 63.8 (t; CH2O), 85.5 (d;
ꢀ
CHNO2), 117.2 (s; C N), 163.2 ppm (s; C=O); IR (film): n˜ =2986, 2250
(C N), 1749 (C=O), 1564 (NO2), 1442, 1372 cmÀ1; MS (EI): m/z (%): 187
ꢀ
(<1) [M+1]+,159 [MÀHCN]+, 141 (12) [MÀOEt]+, 68 (100); elemental
analysis calcd (%) for C7H10N2O4 (186.17): C 45.16, H 5.41, N 15.05;
found: C 45.38, H 5.62, N 14.90.
1.04 g] in a NMR tube containing CuACHTNUGTRENUNG(OAc)2 (1.9 mg) and this was set
aside at 608C for 30 min, thus allowing the salt to enter into solution.
Methyl acrylate (2a, 19 mL) was then added and the tube was inserted
into the NMR probe maintained at 608C.[45]
Concentration evaluation: An array of 1H NMR spectra, recorded at in-
tervals of 30 min until no further spectral changes were observed, was
collected for every run and the concentrations were evaluated by integra-
tion of the signal for 4-H of the cycloadduct 4a (m, 3.47–3.51 ppm) and
one of the ethylenic proton signals of methyl acrylate (2a, m, 6.00–
6.22 ppm). Formation of the cycloadduct 4a was assumed to be the only
process involving the dipolarophile 2a.
Nitro compound 3d (ethyl 4-benzenesulfonyl-2-nitrobutanoate)
(entry 12, Table 1): Treatment of phenyl vinyl sulfone (2d, 71.5 mg) by
the general procedure gave 3d (105 mg, 82%) as a pale yellow oil after
96 h and chromatographic purification (elution first with petroleum ether
1
and then with petroleum ether/ethyl acetate 3:1, Rf =0.28). H NMR: d=
1.27 (t, J=7.2 Hz, 3H; CH3CH2O), 2.61 (q, J=7.2 Hz, 2H; CHCH2),
3.21 (t, J=6.8 Hz, 2H; CH2SO2), 4.27 (q, J=7.2 Hz, 2H; CH3CH2O),
5.38 (7, J=8.0 Hz, 1H; CHNO2), 7.58 (m, 2H; Ph-H), 7.68 (m, 1H; Ph-
H), 7.89 ppm (m, 2H; Ph-H); 13C NMR: d=13.8 (q; CH3CH2), 23.7 (t;
CHCH2), 51.6 (t; CH2SO2), 63.5 (t; CH2O), 85.3 (d; CHNO2), 128.0 (d,
2C; Ph-C), 129.6 (d, 2C; Ph-C), 134.3 (d, Ph-C), 138.2 (s, Ph-C),
163.4 ppm (s; C=O); IR (CDCl3): n˜ =3070, 2985, 1803, 1752 (C=O), 1565,
1447, 1308, 1153 cmÀ1; MS (EI): m/z (%): 160 (80) [MÀSO2Ph]+, 132
(44), 77 (100) [Ph]+; elemental analysis calcd (%) for C12H15NO6S
(301.32): C 47.83, H 5.02, N 4.65; found: C 47.80, H 5.20, N 4.71.
General procedure for the preparation of nitro compounds 3a–e: Olefin
(0.424 mmol) was added to a mixture of ethyl nitroacetate (1, 141 mg,
1.06 mmol) and variously DABCO (4.8 mg, 0.0424 mmol, for 2a, 2b and
2d), DBU (6.5 mg, 0.0424 mmol, for 2c) or N-methylpiperidine (4.2 mg,
0.0424 mmol, for 2e) in chloroform (1.4 mL), and the mixture was mag-
netically stirred in a sealed vessel at 308C (unless otherwise stated).
After the indicated time the reaction mixture was concentrated and the
residue was purified by chromatography on silica gel with the indicated
eluent.
Nitro compound 3e (ethyl 2-nitro-5-oxo-hexanoate) (entry 15, Table 1):
Treatment of methyl vinyl ketone (2e, 30 mg, 35 mL) by the general pro-
cedure gave 3e (43 mg, 50%) as a clear oil after 18 h (608C) and chro-
matographic purification (elution first with petroleum ether and then
with petroleum ether/ethyl acetate 5:1, Rf =0.21). 1H NMR: d=1.28 (t,
J=7.2 Hz, 3H; CH3CH2O), 2.14 (s, 3H; CH3CO), 2.38–2.46 (m, 2H;
CH2CH), 2.54–2.64 (m, 2H; CH2CO), 4.26 (q, J=7.2 Hz, 2H;
CH3CH2O), 5.21 ppm (dd, J=6.4 and 8.4 Hz, 1H; CHNO2); 13C NMR:
d=13.8 (q; CH3CH2), 24.0 (t; CH2CH), 29.9 (q; CH3CO), 38.3 (t;
CH2CO), 63.1 (t; CH2O), 86.7 (d; CHNO2), 164.2 (s; CO2Et), 205.9 ppm
(s; CH3CO); IR (CDCl3): n˜ =2986, 1751 (C=O), 1719 (C=O), 1564 (N=
O), 1371 (N=O) cmÀ1; MS (EI): m/z (%): 188 (2) [MÀCH3]+, 160 (1)
[MÀCOMe]+, 156 (2) [MÀHNO2]+, 115 (10), 114 (10), 101 (30), 85 (78),
73 (47), 69 (20), 55 (100); elemental analysis calcd (%) for C8H13NO5
(203.19): C 47.29, H 6.45, N 6.89; found: C 47.65, H 6.58, N 6.85.
General procedure for the preparation of 4,5-dihydroisoxazoles 4a–j
(Table 3): Olefin (0.424 mmol) was added to a mixture of copper(II) ace-
tate (3.9 mg, 0.0212 mmol), ethyl nitroacetate (1, 86 mg, 0.636 mmol for
2a–e; 141 mg, 1.06 mmol for 2h–j) and N-methylpiperidine (4.2 mg,
0.0424 mmol, unless otherwise stated) in chloroform (1.4 mL), and the
mixture was magnetically stirred in a sealed vessel at 608C. After the in-
dicated time the reaction mixture was concentrated and the residue was
purified by chromatography on silica gel with the indicated eluent.
Nitro compound 3a [1-ethyl 5-methyl 2-nitropentanedioate] (entry 1,
Table 1): Treatment of methyl acrylate (2a, 37 mg, 38 mL) by the general
procedure gave 3a (80 mg, 86%) as a clear oil after 240 h and chromato-
graphic purification (elution first with hexane and then with hexane/ethyl
acetate 5:1, Rf =0.32). 1H NMR: d=1.31 (t, J=6.0 Hz, 3H; CH3CH2O),
2.56–2.45 (m, 4H; CH2CH and CH2CO), 3.70 (s, 3H; CH3O), 4.29 (q, J=
6.0 Hz, 2H; CH3CH2O), 5.33–5.26 ppm (m, 1H; CHNO2); 13C NMR: d=
13.9 (q; CH3CH2), 25.3 (t; CH2CH), 29.4 (t; CH2CO), 52.0 (q; CH3O),
63.2 (t; CH2O), 86.7 (d; CHNO2), 164.1 (s; C=O), 171.9 ppm (s; C=O);
IR (CDCl3): n˜ =2986, 2955, 1749 (C=O), 1564 (NO2), 1439, 1372 (NO2),
1208 cmÀ1; MS (EI): m/z (%): 188 (16) [MÀOCH3]+, 173 (13) [MÀNO2]+,
160 (3) [MÀCO2Me]+, 127 (38), 113 (22), 100 (25), 85 (41), 59 (100)
[CO2Me]+; elemental analysis calcd (%) for C8H13NO6 (219.19): C 43.84,
H 5.98, N 6.39; found: C 43.94, H 5.85, N 6.46.
Isoxazoline 4a [4,5-dihydro-isoxazole-3,5-dicarboxylic acid 3-ethyl ester
5-methyl ester]: Treatment of methyl acrylate (2a, 37 mg, 38 mL) by the
general procedure gave 4a (76 mg, 89%) as a clear oil after 20 h and
chromatographic purification (elution first with hexane and then with
hexane/ethyl acetate 4:1, Rf =0.14). 1H NMR: d=1.34 (t, J=7.2 Hz, 3H;
CH3CH2O), 3.47–3.51 (m, 2H; 4-H), 3.79 (s, 3H; CH3O), 4.33 (q, J=
7.2 Hz, 2H; CH3CH2O), 5.17 ppm (dd, J=8.2 and 11.4 Hz, 1H; 5-H);
13C NMR: d=14.0 (q; CH3), 37.6 (t; C-4), 52.9 (q; CH3O), 62.4 (t;
OCH2), 79.7 (d; C-5), 151.4 (s; C-3), 159.8 (s; CO2Et), 169.3 ppm (s;
CO2Me); IR (film): n˜ 2295, 2958, 1741 (C=O), 1598, 1439 cmÀ1; MS (EI):
Nitro compound 3b [ethyl 5-(dimethylamino)-2-nitro-5-oxopentanoate]
(entry 5, Table 1): Treatment of N,N-dimethylacrylamide (2b, 42 mg,
44 mL) by the general procedure gave 3b (23 mg, 23%) as a pale yellow
oil after 240 h and chromatographic purification [elution first with
hexane and then gradient with ethyl nitroacetate/hexane from 33% (1:2)
to 50% (1:1) (Rf =0.20). 1H NMR: d=1.28 (t, J=6.8 Hz, 3H;
CH3CH2O), 2.32–2.58 (m, 4H; CH2CH and CH2CO), 2.92 (s, 3H;
NCH3), 2.94 (s, 3H; NCH3), 4.25 (q, J=6.8 Hz, 2H; CH3CH2O),
5.40 ppm (dd, J=5.2 and 9.6 Hz, 1H; CHNO2); 13C NMR: d=13.9 (q;
CH3CH2), 25.7 (t; CH2CH), 28.3 (t; CH2CO), 35.4 (s; NCH3), 36.9 (s;
NCH3), 63.0 (t; CH2O), 87.2 (d; CHNO2), 164.5 (s; C=O), 170.2 ppm (s;
C=O); IR (film, neat): n˜ =2940, 1749 (C=O), 1644 (C=O),1564 (NO2),
m/z (%): 202[46] (<1) [M+1]+ 201 (<1) [M]+, 156 (36) [MÀOEt]+, 142
,
(100) [MÀCO2Me]+, 70 (60), 59 (93) [CO2Me]+; elemental analysis calcd
(%) for C8H11NO5 (201.18): C 47.76, H 5.51, N 6.96; found: C 47.36, H
5.65, N 7.27.
Isoxazoline 4b {ethyl 5-[(dimethylamino)carbonyl]-4,5-dihydro-isoxazole-
3-carboxylate}: Treatment of N,N-dimethylacrylamide (2b, 42 mg, 44 mL)
by the general procedure gave 4b (92 mg, 100%) as a clear oil after 20 h
and chromatographic purification (elution first with hexane and then
with hexane/ethyl acetate 1:1, Rf =0.15). 1H NMR: d=1.33 (t, J=7.0 Hz,
3H; CH3CH2O), 2.98 (s, 3H; NCH3), 3.15 (s, 3H; NCH3), 3.23 (dd, J=
11.7 and 17.9 Hz, 1H; 4-H), 3.99 (dd, J=11.7 and 17.9 Hz, 1H; 4-H),
4.31 (q, J=7.0 Hz, 2H; CH3CH2O), 5.41 ppm (dd, J=8.0 and 11.7 Hz,
1H; 5-H); 13C NMR: d=14.0 (q; CH3), 35.7 (t; C-4), 36.2 (s; NCH3), 37.2
(s; NCH3), 62.1 (t; OCH2), 79.9 (d; C-5), 152.2 (s; C-3), 160.1 (s; C=O),
166.2 ppm (s; C=O); IR (CDCl3): n˜ 2984, 2940, 1723 (C=O), 1657 (C=O),
1598, 1566, 1405, 1253 cmÀ1; MS (EI): m/z (%): 214 (2) [M]+, 184 (14),
169 (3) [MÀOEt]+, 114 (10), 72 (100) [CONMe2]+; elemental analysis
calcd (%) for C9H14N2O4 (214.219): C 50.46, H 6.59, N 13.08; found: C
50.74, H 6.58, N 13.06.
1439, 1372, 1258 cmÀ1 MS (EI): m/z (%): 232 (2) [M]+, 185 (14)
;
[MÀNO2]+, 140 (18), 113 (25), 72 (100) [CONMe2]+; elemental analysis
calcd (%) for C9H16N2O5 (232.23): C 46.55, H 6.94, N 12.06; found: C
46.36, H 6.80, N 11.81.
Nitro compound 3c (ethyl 4-cyano-2-nitrobutanoate) (entry 9, Table 1):
Treatment of acrylonitrile (2c, 22.5 mg, 28 mL, 0.424 mmol) by the gener-
al procedure gave 3c (61 mg, 77%) as a clear oil after 18 h and chroma-
tographic purification (elution first with hexane and then with hexane/
acetone 5:1) (Rf =0.13). 1H NMR: d=1.33 (t, J=8.0 Hz, 3H;
Chem. Eur. J. 2009, 15, 7940 – 7948
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7945

F. Machetti, F. De Sarlo, and E. Trogu
Isoxazoline 4c [ethyl 5-cyano-4,5-dihydro-isoxazole-3-carboxylate]: Treat-
ment of acrylonitrile (2c, 23 mg, 28 mL) by the general procedure gave 4c
(60 mg, 85%) as a clear oil[47,48] after 20 h and chromatographic purifica-
tion (elution first with hexane and then with hexane/ethyl acetate 4:1,
Rf =0.18). 1H NMR: d=1.36 (t, J=7.2, 3H; CH3CH2O), 3.60 (d, J=
7.6 Hz, 1H; 4-H), 3.62 (d, J=10.8 Hz, 1H; 4-H), 4.36 (q, J=7.2 Hz, 2H;
CH3CH2O), 5.36 ppm (dd, J=7.6 and 10.8 Hz, 1H; 5-H); 13C NMR: d=
14.0 (q; CH3), 39.9 (t; C-4), 62.9 (t; OCH2), 68.0 (d; C-5), 115.8 (s; CN),
Isoxazolines 4g [4-methyl-4,5-dihydro-isoxazole-3,5-dicarboxylic acid 3-
ethyl ester 5-methyl ester] and 5g [5-methyl-4,5-dihydro-isoxazole-3,4-di-
carboxylic acid 3-ethyl ester 4-methyl ester]: The reaction mixture ob-
tained after 70 h from methyl (E)-crotonate (2g, 43 mg, 45 mL) by the
general procedure was concentrated under reduced pressure, the residue
was taken up with diethyl ether (20 mL), and the solution was washed
with aq. HCl (5%, 10 mL), water (10 mL), sat. Na2CO3 solution (10 mL)
and brine (10 mL). The organic layer was then dried over Na2SO4, fil-
tered and concentrated. Chromatographic purification (petroleum ether/
ethyl acetate 25:1, then petroleum ether/ethyl acetate 10:1 as eluent, Rf =
0.14) gave a mixture of 4g and 5g (69 mg, 76%) as a colourless oil. Inte-
gration of the 5-H protons in the 1H NMR spectrum showed the 4g/5g
ratio to be 1.8:1. Elemental analysis calcd (%) for C9H13NO5 (215.20): C
50.23, H 6.09, N 6.51; found: C, 50.19, H 6.06, N 6.88.
ꢀ
151.1 (s; C-3), 158.9 ppm (s; C=O); IR (neat): n˜ =2986, 2245 (C N),
1724 (C=O), 1602, 1382, 1271, 1124 cmÀ1; MS (EI): m/z (%): 168 (4)
[M]+, 140 (11) [MÀHCN]+, 123 (100) [MÀOEt]+, 113 (49), 110 (10), 96
(18), 95 (10) [MÀCO2Et]+; elemental analysis calcd (%) for C7H8N2O3
(168.15): C 50.00, H 4.80, N 16.66; found: C 49.90, H 4.46, N 16.47.
Isoxazoline 4d [ethyl 5-benzenesulfonyl-4,5-dihydro-isoxazole-3-carboxyl-
ate]: Treatment of ethenesulfonylbenzene (2d, 72 mg) by the general pro-
cedure gave 4d (99 mg, 83%) as a white solid after 20 h and chromato-
graphic purification (elution first with petroleum ether and then with pe-
troleum ether/ethyl acetate 4:1, Rf =0.14). M.p. 87–888C. 1H NMR: d=
1.33 (t, J=7.2 Hz, 3H; CH3CH2O), 3.63 (dd, J=11.4 and 19.6 Hz, 1H; 4-
H), 3.92 (dd, J=5.2 and 19.2 Hz, 1H; 4-H), 4.32 (q, J=7.2 Hz, 2H;
CH3CH2O), 5.53 (dd, J=4.8 and 11.2 Hz, 1H; 5-H), 7.59 (m, 2H; Ph-H),
7.70 (m, 1H; Ph-H), 7.96 ppm (m, 2H; Ph-H); 13C NMR: d=14.0 (q;
CH3), 35.7 (t; C-4), 62.7 (t; OCH2), 94.0 (d; C-5), 129.4 (d, 2C; Ph-C),
129.8 (d, 2C; Ph-C), 134.8 (Ph-C), 134.9 (Ph-C), 152.0 (s; C-3),
158.8 ppm (s; C=O); IR (CDCl3): n˜ =2985, 1726 (C=O), 1604, 1448, 1326,
1269, 1155 cmÀ1; MS (EI): m/z (%): 283 (<1) [M]+, 238 (2) [MÀOEt]+,
1
Isoxazoline 4g: H NMR: d=1.34 (t, J=6.8 Hz, 3H; CH3CH2O), 1.41 (d,
J=7.2 Hz, 3H; CH3), 3.72–3.76 (m, 1H; 4-H), 3.77 (s, 3H; CH3O), 4.32
(q, J=6.8 Hz, 2H; CH3CH2O), 4.73 ppm (d, J=6.0 Hz, 1H; 5-H);
13C NMR: d=14.0 (q; CH3), 17.5 (q; CH3), 46.3 (t; C-4), 52.8 (q; CH3O),
62.2 (t; OCH2), 86.4 (d; C-5), 154.6 (s; C-3), 159.6 (s; CO2Et), 169.4 ppm
(s; CO2Me); GC-MS (EI): m/z (%): 216 (<1) [M+1]+, 170 (12)
[MÀOEt]+, 156 (38) [MÀCO2Me]+, 128 (4), 84 (34), 59 (68) [CO2Me]+,
56 (100).
1
Isoxazoline 5g: H NMR: d=1.33 (t, J=7.2 Hz, 3H; CH3CH2O), 1.46 (d,
J=6.4 Hz, 3H; CH3), 3.74 (s, 3H; CH3O), 3.90 (d, J=7.6 Hz, 2H; 4-H),
4.33 (q, J=7.2 Hz, 2H; CH3CH2O), 4.96–5.04 ppm (m, 1H; 5-H);
13C NMR: d=14.0 (q; CH3), 20.4 (q; CH3), 58.2 (t; C-4), 53.0 (q; CH3O),
62.3 (t; OCH2), 84.6 (d; C-5), 149.1 (s; C-3), 159.9 (s; CO2Et), 169.0 ppm
(s; CO2Me); GC-MS (EI): m/z (%): 216 (<1) [M+1]+, 200(<1)
[MÀMe]+, 184 (2) [MÀOMe]+, 170 (4) [MÀOEt]+, 156 (8)
[MÀCO2Me]+, 142 (4) [MÀCO2Et]+, 128 (44), 116 (52), 101 (36), 100
(54), 59 (100) [CO2Me]+.
142 [MÀSO2Ph]+, 114 (90), 96 (62), 78 (58), 77
(100) [Ph]+; elemental
ACHTUNGTRENNUNG
analysis calcd (%) for C12H13NO5S (283.30): C 50.87, H 4.63, N 4.94;
found: C, 50.59, H 4.74, N 5.05.
Isoxazoline 4e [ethyl 5-acetyl-4,5-dihydro-isoxazole-3-carboxylate]:
Treatment of methyl vinyl ketone (2e, 30 mg, 35 mL) by the general pro-
cedure gave a mixture of the nitro compound 3e and the isoxazoline 4e
(72 mg, 3e: 26%, 4e: 64%) as a clear oil after 18 h and chromatographic
purification (elution first with petroleum ether and then with petroleum
ether/ethyl acetate 5:1, Rf =0.21). Integration of the OCH3 protons in the
1H NMR spectrum showed the 3e/4e ratio to be 1:2.5. A further chroma-
tographic separation with a different eluent (CH2Cl2/hexane 5:3) allowed
the isoxazoline 4e (Rf =0.19)[49] to be partially separated. 1H NMR: d=
1.35 (t, J=7.2 Hz, 3H; CH3CH2O), 2.31 (s; CH3CO), 3.34 (dd, J=12.2
and 18.2 Hz, 1H; 4-H), 3.49 (dd, J=7.2 and 18.2 Hz, 1H; 4-H), 4.34 (q,
J=7.2 Hz, 2H; CH3CH2O), 5.07 ppm (dd, J=12.2 and 7.2 Hz, 1H; 5-H);
13C NMR: d=13.8 (q; CH3CH2), 26.4 (q; CH3CO), 35.7 (t; C-4), 62.3 (t;
OCH2), 86.0 (d; C-5), 151.6 (s; C-3), 159.7 (s; CO2Et), 205.1 ppm (s;
COMe); IR (CDCl3): n˜ =2984, 1726 (C=O), 1595, 1562 cmÀ1; GC-MS
(EI): m/z (%): 185 (31) [M+], 142 (40) [MÀCOMe]+, 140 (66), 115 (29),
114 (16), 112 (27) [MÀCO2Et]+, 96 (18), 70 (100), 55 (66); elemental
analysis calcd (%) for C8H11NO4 (185.18): C 51.89, H 5.99, N 4.57; found:
C, 52.10.59, H 5.79, N 7.82.
Reaction between dimethyl maleate and ethyl nitroacetate—isoxazolines
4h [(4SR)-(5RS)-4,5-dihydro-isoxazole-3,4,5-tricarboxylic acid 3-ethyl
ester 4,5-dimethyl ester], isoxazolines 4i [(4SR)-(5SR)-4,5-dihydro-isoxa-
zole-3,4,5-tricarboxylic acid 3-ethyl ester 4,5-dimethyl ester] and isoxa-
zole 6 [isoxazole-3,4,5-tricarboxylic acid 3-ethyl ester 4,5-dimethyl ester]:
Treatment of dimethyl maleate (2h, 61 mg, 53 mL) by the general proce-
dure gave the isoxazole 6 (Rf =0.29, 8 mg, 7%) and the isoxazoline 4i (Rf
<0.1, 87 mg, 79%) as a clear oil after 24 h and chromatographic purifica-
tion (elution first with hexane and then with hexane/ethyl acetate 5:1).
GC-MS analysis showed the presence of less than 10% of the isomer 4h.
Compound 4h: Identified signals. 1H NMR: 3.74 (s, 3H; CH3O), 3.79 (s,
3H; CH3O), 5.41 (d, J=9.9 Hz, 1H; 5-H), 4.64 ppm (d, 1H; J=9.9 Hz, 4-
H); 13C NMR: d=14.2 (q; CH3), 53.0 (q; CH3O), 53.2 (q; CH3O), 55.4
(d; C-4), 62.2 (t; OCH2), 82.5 (d; C-5), 150.7 (s; C-3), 159.0 (s; CO2Et),
166.7 (s; CO2Me), 166.8 ppm (s; CO2Me); GC MS (EI): m/z (%): 260 (<
1) [M+1]+, 228 (2), 200 (10), 172 (4), 156 (16), 128 (33), 100 (24), 59
(100).
Isoxazoline 4 f [5-methyl-4,5-dihydro-isoxazole-3,5-dicarboxylic acid 3-
ethyl ester 5-methyl ester]: The reaction mixture obtained after 65 h
from methyl methacrylate (2 f, 43 mg, 45, mL) by the general procedure
[with N-methylmorpholine (4.3 mg) instead of N-methylpiperidine] was
concentrated under reduced pressure, the residue was taken up with di-
ethyl ether (20 mL), and the solution was washed with aq. HCl (5%,
10 mL), water (10 mL), sat. Na2CO3 solution (10 mL) and brine (10 mL).
The organic layer was then dried over Na2SO4, filtered and concentrated.
Chromatographic purification (petroleum ether/ethyl acetate 5:1 as
Compound 4i: 1H NMR: d=1.33 (t, J=7.4 Hz, 3H; CH3CH2O), 3.78 (s,
3H; CH3O), 3.81 (s, 3H; CH3O), 3.90 (d, J=7.6 Hz, 1H; 4-H), 4.34 (q,
J=7.4 Hz, 2H; CH3CH2O), 4.63 (d, 1H; J=6.2 Hz, 4-H), 5.36 ppm (d,
J=6.2 Hz, 1H; 5-H); 13C NMR: d=14.1 (q; CH3), 53.4 (q; CH3O), 53.5
(q; CH3O), 55.2 (d; C-4), 62.2 (t; OCH2), 83.4 (d; C-5), 148.9 (s; C-3),
158.8 (s; CO2Et), 167.7 (s; CO2Me), 167.8 ppm (s; CO2Me); IR (CDCl3):
n˜ =2985, 2956, 1748 (C=O), 1597, 1437 cmÀ1; GC MS (EI): m/z (%): 260
(<1) [M+1]+, 228 (2), 214 (4), 200 (22), 172 (12), 100 (32), 101 (26), 59
(100) [CO2Me]+; elemental analysis calcd (%) for C10H13NO7 (259.21): C
46.34, H 5.06, N 5.40; found: C 46.17, H 5.39, N 5.78.
1
eluent, Rf =0.23) gave 4 f (84 mg, 93%) as a colourless oil. H NMR: d=
1.34 (t, J=7.2 Hz, 3H; CH3CH2O), 1.66 (s, 3H; 5-CH3), 3.64 (d, J=
18.0 Hz, 1H; 4-H), 3.70 (d, J=18.0 Hz, 1H; 4-H), 3.79 (s; CH3O),
4.32 ppm (q, J=7.2 Hz, 2H; CH3CH2O); 13C NMR: d=14.0 (q;
CH2CH3), 23.4 (q; CH3), 43.4 (t; C-4), 53.1 (t; OCH3), 62.2 (q; OCH2),
88.4 (s; C-5), 151.0 (s; C-3), 160.1 (s; CO2Et), 171.1 ppm (s; CO2Me); IR
(CDCl3): n˜ =2985, 2956, 1740 (C=O), 1595, 1265 cmÀ1; MS (EI): m/z (%):
216 (<1) [M+1]+, 215 (<1) [M]+, 200(<1) [MÀMe]+, 170 (35)
[MÀOEt]+, 156 (64) [MÀCO2Me]+, 84 (64), 73 (28) [CO2Et]+, 59 (100)
[CO2Me]+; elemental analysis calcd (%) for C9H13NO5 (215.20): C 50.23,
H 6.09, N 6.51; found: C, 50.10, H 6.36, N 6.88.
Compound 6: 1H NMR: d=1.38 (t, J=7.2 Hz, 3H; CH2CH3), 3.94 (s,
3H; OCH3), 3.98 (s, 3H; OCH3), 4.43 ppm (q, J=7.2 Hz, 2H; CH2CH3);
13C NMR: d=13.9 (q; CH2CH3), 53.4 (q; OCH3), 53.6 (q; OCH3), 63.1 (t;
CH2CH3), 117.8, (s; C-4), 154.4 (s), 155.5 (s), 157.9 (s; CO2Me), 158.9 (s;
CO2Et), 160.1 ppm (s; CO2Me); IR (CDCl3): n˜ =2986, 2956, 1747 (C=O),
1608, 1478, 1434 cmÀ1; MS (EI): m/z (%): 257 (<1) [M]+, 226 (14) [MÀ
OMe]+ 198 (4) [MÀCO2Me]+, 126 (65), 59 (100) [CO2Me]+; elemental
,
analysis calcd (%) for C10H11NO7 (257.20): calcd C 46.70, H 4.31, N 5.45;
found C 46.64, H 4.70, N 5.69.
7946
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 7940 – 7948

Michael Additions versus Cycloaddition Condensations
FULL PAPER
Reaction between dimethyl fumarate and ethyl nitroacetate—isoxazoline
4i and isoxazole 6: Dimethyl fumarate (2i, 61.2 mg, 0.424 mmol) was
added to a mixture of copper(II) acetate (3.9 mg, 0.0212 mmol,) ethyl ni-
troacetate (141 mg, 1.06 mmol) and 1-methylpiperidine (4.2 mg,
0.0424 mmol) in chloroform (1.4 mL) and the mixture was magnetically
stirred in a sealed vessel at 608C. After 69 h further quantities of cop-
per(II) acetate (3.9 mg, 0.0212 mmol) and 1-methylpiperidine (4.2 mg,
0.0424 mmol) were added and the reaction mixture was heated for 62 h
longer. The reaction mixture was concentrated and the residue was puri-
fied by chromatography on silica gel with elution first with hexane and
then with hexane/ethyl acetate 5:1. A first fraction (Rf =0.29) containing
the isoxazole 6 (65 mg, 60%) was followed by a second fraction contain-
ing the isoxazoline 4i [Rf <0.1, 33 mg] as clear oil in 30% yield. GC-MS
analysis of the latter fraction showed the presence of less than 10% of
isomer 4h.
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Compound 4i: Spectroscopic data are identical to those reported above
for compound 4i obtained from dimethyl maleate. Elemental analysis
calcd (%) for C10H13NO7 (259.21): C 46.34, H 5.06, N 5.40; found: C
46.64, H 4.70, N 5.69.
Compound 6: Spectroscopic data are identical to those reported above
for compound 6 obtained from dimethyl maleate. Elemental analysis
calcd (%) for C10H11NO7 (257.20): C 46.70, H 4.31, N 5.45; found: C
46.95, H 4.62, N 5.72.
Isoxazoline 4j [4,5-dihydro-isoxazole-3,4,5-tricarboxylic acid 3-ethyl ester
4,5-dimethyl ester]: Treatment of N-phenylmaleimide (2j, 74 mg) by the
general procedure gave 4j (87 mg, 71%) as a yellowish powder after 64 h
and chromatographic purification (elution first with hexane and then
with hexane/ethyl acetate 3:1, Rf =0.11). M.p. 174–1758C; 1H NMR: d=
1.38 (t, J=7.2 Hz, 3H; CH3CH2O), 4.38–4.46 (m, 2H; CH3CH2O), 4.86
[d, J=10.0 Hz; C(=N)CH], 5.68 (d, J=10.0 Hz; OCH), 7.25–7.28 (m,
2H; Ph-H), 7.38–7.50 ppm (m, 3H; Ph-H); 13C NMR: d=14.0 (q;
CH2CH3), 53.7 (d; C(=N)CH), 63.1 (t; CH3CH2O), 82.0 (d; OCH), 126.1
(d, 2C; Ph-C), 129.4(d, 2C; Ph-C), 130.6 (s, Ph-C), 147.7 (s; C=N), 158.2
(s; CO2Et), 168. 9 (s; NCO), 169.2 ppm (s; NCO); IR (CDCl3): n˜ =1737
(C=O), 1584, 1498, 1378 cmÀ1; MS (EI): m/z (%): 288 (12) [M]+ 243 (2),
119 (100), 91 (16), 77 (6); elemental analysis calcd (%) for
C14H12N2O5·H2O (288.26): C 58.33, H 4.20, N 9.72; found: C 58.73 H 4.26,
N 9.36.
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Received: December 17, 2008
Published online: April 22, 2009
7948
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Chem. Eur. J. 2009, 15, 7940 – 7948