Solid base-catalyzed synthesis of 5-substituted 4,5-dihydroisoxazoles

Article abstract of DOI:10.1016/j.tetlet.2005.07.071

We present a new synthetic route for the preparation of 5-substituted 4,5-dihydroisoxazole derivatives starting from ethyl nitroacetate and alkenes in the presence of modified Mg:Al 3:1 hydrotalcite.

Full text of DOI:10.1016/j.tetlet.2005.07.071

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6563–6566
Solid base-catalyzed synthesis of 5-substituted
4,5-dihydroisoxazoles
a
a,
b
a
*
´
´
Agnieszka Cwik, Zoltan Hell, Aliz Fuchs and Dora Halmai
aDepartment of Organic Chemical Technology, Budapest University of Technology and Economics, H-1521 Budapest, Hungary
bResearch Group for Organic Chemical Technology, Hungarian Academy of Sciences, H-1521 Budapest, Hungary
Received 18 March 2005; revised 4 July 2005; accepted 15 July 2005
Abstract—We present a new synthetic route for the preparation of 5-substituted 4,5-dihydroisoxazole derivatives starting from ethyl
nitroacetate and alkenes in the presence of modified Mg:Al 3:1 hydrotalcite.
Ó 2005 Elsevier Ltd. All rights reserved.
4,5-Dihydroisoxazoles are an important class of hetero-
cyclic compounds. They can be converted into several
useful synthetic units such as b-hydroxy ketones,1 c-ami-
no alcohols,2 a,b-unsaturated oximes,3 and b-hydroxy
nitriles.4 Moreover, isoxazole derivatives have biological
activities and pharmacological properties such as hypo-
glycemic,5 antibacterial,6 or anti-inflammatory.7
COOEt
R
R''
R
R''
K2CO3
+
R'
EtOOC
R'''
I2, PTC
toluene
COOEt
1
R'''
R'
COOEt
2
3
Scheme 1.
It is well-known that nitrile oxides undergo [3+2] cyclo-
addition with olefins to provide isoxazole derivatives.8
Several methods have been described in the literature
for the in situ generation of nitrile oxides. The most pop-
ular are MukaiyamaÕs method using phenyl isocyanate
with a catalytic amount of Et3N for the dehydration
of primary nitro compounds9 and the Huisgen base-
induced dehydrohalogenation of hydroximoyl chlo-
rides.10 However, nitrile oxides are unstable and dimer-
ize readily to form 3,4-diacetyl-1,2,5-oxadiazole 2-oxides
(named as furoxans).11 There are also other methods for
the preparation of isoxazole derivatives such as nitrosa-
tive cyclization using a DMSO solution of sodium nitrite
and n-propyl nitrite,12 reactions of 2,3-disubstituted
cyclopropanes with NOBF4,13 or treatment of isoxazo-
lin-5-ones with olefins.14
3 (Scheme 1), which involved the reaction of CH-acids
with non-activated olefins 2 in the presence of solid
potassium carbonate, a lipophilic quaternary ammo-
nium salt as phase transfer catalyst and iodine.15
The reaction is a complex, SET-induced process with
more than 10 elemental steps. Starting from malonic
acid allylic esters, bicyclic cyclopropane carboxylic acid
lactones were formed in a stereoselective intramolecular
cyclization in good yield.16 During our later studies it
was found that non-activated Mg:Al 3:1 hydrotalcite
(HT) was also a suitable basic catalyst for this intra-
molecular cyclization reaction even without the phase
transfer catalyst.17
The hydrotalcites are anionic layered double hydroxides
(LDHs). Their structures consist of brucite Mg(OH)2
type octahedral layers in which a part of the M(II)
cations are substituted by M(III) cations. The excess
positive charge is compensated by different anions such
as hydroxyl, carbonate, halogen, nitrate, etc.18 In gen-
eral, the activation of HT consists of two steps. First,
upon thermal treatment at 450–500 °C, HT forms a
highly active Mg(Al)O mixed oxide that exhibits strong
Lewis basicity. In the second step the calcined catalyst is
We have developed a phase transfer catalytic method for
the synthesis of cyclopropane carboxylic acid derivatives
Keywords: Layered double hydroxides; Hydrotalcite; 4,5-Dihydrois-
oxazoles.
*
Corresponding author. Tel.: +36 1 463 1414; fax: +36 1 463 3648;
e-mail: zhell@mail.bme.hu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.071

6564
A. Cwik et al. / Tetrahedron Letters 46 (2005) 6563–6566
Table 1. Results of the preparation of ethyl 5-butyl-4,5-dihydro-3-
isoxazole carboxylate 6 with various catalystsa
rehydrated which, due to its memory effect, results in the
restoration of the original HT structure with OHÀ
groups, giving a Brønsted type catalyst.19 We have
recently reported, the cyclization of bis-ketonic Man-
nich bases,20 investigation of the Henry reaction21 and
the synthesis of oxazolidin-2-ones22 catalyzed by differ-
ent types of Mg:Al hydrotalcites.
Entry
Catalyst
Reaction
time (h)
Yield (%)
1a
2a
3a
4a
5b
6b
Rehydrated Mg:Al 3:1 HT20
Calcined Mg:Al 3:1 HT
Non-activated Mg:Al 3:1 HT
Non-activated Mg:Al 2:1 HT
K2CO3
7
7
9
9
3
65c
<5c
—
—
11 (12)d
30 (33)d
During the course of our studies toward the catalytic
application of hydrotalcites, we became interested in
examination of the reaction between ethyl nitroacetate
4 and 1-hexene 5. The bases tested in this reaction were
activated and non-activated Mg:Al 3:1 hydrotalcite as
well as the commercially available Mg:Al 2:1 HT. The
reactions were carried out in toluene at 110 °C in the
presence of iodine, which was necessary for the forma-
tion of cyclopropane derivatives.15,17 To our surprise,
none of the expected cyclopropane derivative was
formed. The 1H NMR spectrum showed two double
doublets at d 2.83 ppm (J1 = 8.7 Hz and J2 = 17.4 Hz)
and 3.23 ppm (J1 = 10.8 Hz and J2 = 17.4 Hz) with the
same intensity. The 13C NMR spectrum showed a signal
at 158.2 ppm. Based on these data, the formation of a 5-
substituted 4,5-dihydro-3-isoxazole ring (Scheme 2) was
evident.23 The IR spectrum confirmed the presence of
the C@N bond (1585 cmÀ1).
K2CO3
15
a Reaction conditions: ethyl nitroacetate 0.13 g (1 mmol), hexene 0.09 g
(1.1 mmol), catalyst 0.15 g, catalytic amount of iodine, toluene
(5 ml), 60 °C.
b Reaction conditions: ethyl nitroacetate 0.4 g (3 mmol), hexene 0.25 g
(3 mmol), K2CO3 0.66 g, iodine 0.6 g, toluene (10 ml), one drop of
TCMC, 60 °C.
c Determined by 1H NMR.
d Isolated yield, the values in parentheses refer to the yield of 7.
We next investigated the reactivity of a variety of olefins
with ethyl nitroacetate in the presence of rehydrated
Mg:Al 3:1 HT. The corresponding 4,5-dihydroisoxazole
derivatives were obtained in all cases (Table 2).
The identity of the products was confirmed by 1H NMR
and 13C NMR spectroscopic analysis. The results are
summarized in Table 2.
When rehydrated Mg:Al 3:1 HT was used, which is a
strong Brønsted base, ethyl 5-butyl-4,5-dihydro-3-isox-
azole carboxylate 6 was obtained in 65% yield.24 The
non-activated HT with carbonate as the compensating
anion failed to give any product, only unchanged start-
ing material was recovered. With calcined HT, prepared
by heating at 450 °C for 8 h giving a mixed oxide of Mg
and Al, only very small amounts of the product were
observed (Table 1, entry 2). An increase in the amount
of iodine did not increase the yield.
In all cases the reactions were regioselective and led to
the formation of the 5-substituted isoxazolines exclu-
sively, as suggested by the lowfield values of the CH sig-
nal around d 4.0–5.0 ppm.28 The reaction of cyclohexene
(Table 2, entry 6) with ethyl nitroacetate furnished the
desired bicyclic product, albeit in low yield.
In our reactions we did not detect furoxans. This might
be a quasi high dilution effect due to nitrile oxide for-
mation happening on the solid surface. However, this
by-product would have been formed exclusively from
the nitrile oxide, so as its presence was undetectable,
we might also suppose that in the presence of hydro-
talcites the reaction goes via another intermediate.
When iodine was omitted from the reaction mixture
no reaction occurred. During the investigation of the
mechanism of the cyclopropanation reaction, we
showed the participation of iodomalonic esters and
their reaction in a SET-induced process.15 Since ethyl
nitroacetate is a strong CH-acid, we can assume an
analogous mechanism for this cyclization. The absence
of the cyclopropane as a product can be explained by
tautomerism of ethyl nitroacetate into the aci form,
which might induce one oxygen to participate in ring
formation.
On replacing rehydrated Mg:Al 3:1 HT by potassium
carbonate under the same reaction conditions, ethyl 5-
butyl-4,5-dihydro-3-isoxazole carboxylate 6 was also
obtained but in only a small amount. The other product
detected in this reaction was diethyl 1,2-dinitro-ethane-
1,2-dicarboxylate 7, which is the dimerization product
of ethyl nitroacetate. This kind of dimer is a known
product in the reaction of CH-acids in the presence of
iodine under basic conditions.25,26 Increasing the reac-
tion time led to a considerable increase in the yield of
6 and 7 (Table 1, entry 6). The two compounds can be
separated easily; while 6 is soluble in toluene, 7 precipi-
tates onto the surface of potassium carbonate. Treat-
ment of the solid with acetone yielded pure 7. Other
bases (e.g., KF on alumina, DBU, and triethylamine)
gave no product.
In conclusion, rehydrated Mg:Al 3:1 hydrotalcite is a
suitable catalyst for the cyclization of ethyl nitroacetate
and olefins into 4,5-dihydroisoxazole derivatives. In
contrast to most described methods, this new reaction
may not be a 1,3-dipolar cycloaddition, but rather
a complex, SET-induced radical process similar to
the formation of cyclopropane carboxylic acid
derivatives.15
COOEt
N
EtOOC
HT
O
+
toluene
I2
NO2
4
5
6
Scheme 2.

A. Cwik et al. / Tetrahedron Letters 46 (2005) 6563–6566
6565
Table 2. Reaction between ethyl nitroacetate 4 and various alkenes in the presence of rehydrated Mg:Al 3:1 HTa
Entry
Olefin
Reaction time (h)
Product
Yieldb (%)
24c
N
EtOOC
O
1
25
COOEt
COOEt
N
EtOOC
O
2
20
21c
CN
O
CN
N
N
EtOOC
EtOOC
O
3
4
5
20
20
20
5127
O
O
52c
Ph
N
EtOOC
O
O
O
O
O
55c
O
N
6
25
30c
COOEt
a Reaction conditions: ethyl nitroacetate 0.13 g (1 mmol), alkene (1.1 mmol), catalyst 0.15 g, catalytic amount of iodine, toluene (5 ml), 110 °C.
b Determined by 1H NMR.
c Known products were characterized by comparing the 1H NMR, 13C NMR and IR data with those reported in the literature.
13. Mizuno, K.; Ichinose, N.; Tamai, T.; Otsuji, Y. J. Org.
Chem. 1992, 57, 4669–4675.
Acknowledgment
14. Higashida, S.; Nakashima, H.; Tohda, Y.; Tani, K.;
Nishiwaki, N.; Ariga, M. Heterocycles 1992, 34, 1511–
1513.
This work was supported by the Hungarian Research
Fund Programs (OTKA Grant No. T 037757).
}
´
´
´
15. Toke, L.; Hell, Z.; Szabo, G. T.; Toth, G.; Bihari, M.;
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24. Selected data of ethyl 5-butyl-4,5-dihydro-3-isoxazole car-
boxylate (6): light-yellow oil, 0.13 g (0.65 mmol). IR (neat):
1698, 1585 cmÀ1 1H NMR (300 MHz, CDCl3) d (ppm):
.
0.92 (t, 3H, J = 7.3 Hz), 1.20–1.45 (m, 7H), 1.51–1.64 (m,
1H), 1.72–1.82 (m, 1H), 2.83 (dd, 1H, J = 8.7 Hz, J =
17.4 Hz, CH2), 3.23 (dd, 1H, J = 10.8 Hz, J = 17.4 Hz,
CH2), 4.33 (q, 2H, J = 7.3 Hz), 4.72–4.85 (m, 1H). 13C
NMR (75 MHz, CDCl3) d (ppm): 158.2, 151.5, 84.4, 62.2,
38.5, 34.9, 27.4, 22.5. Anal. Calcd for C10H17NO3: C, 60.30;
H, 8.54; N, 7.03. Found: C, 60.12; H, 8.37; N, 6.94.
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6566
A. Cwik et al. / Tetrahedron Letters 46 (2005) 6563–6566
26. Selected physical data of 7: mp >220 °C, 1H NMR
(300 MHz, CDCl3) d (ppm): 1.23 (t, 6H, J = 7 Hz), 3.59–
3.62 (m, 2H), 4.13 (q, 4H, J = 14.5 Hz).
(neat): 1719, 1587 cmÀ1 1H NMR (300 MHz, CDCl3) d
.
(ppm): 0.90 (t, 3H, J = 7 Hz), 1.15–1.45 (m, 7H), 1.50–
1.62 (m, 2H), 3.21–3.37 (m, 1H), 3.43–3.66 (m, 1H), 4.32
(q, 2H, J = 7.1 Hz), 4.58–4.71 (m, 1H). 13C NMR
(75 MHz, CDCl3) d (ppm): 163.5, 162.0, 88.2, 62.6,
41.4, 35.2, 31.9, 20.0. Anal. Calcd for C10H17NO4: C,
55.81; H, 7.91; N, 6.51. Found: C, 55.67; H, 7.79; N,
6.44.
EtOOC
O2N
NO2
7
COOEt
27. Spectral data of ethyl 5-butoxy-4,5-dihydro-3-isoxa-
zole carboxylate: yellow oil, 0.11 g (0.51 mmol), IR
28. Conti, D.; Rodriguez, M.; Sega, A.; Taddei, M. Tetra-
hedron Lett. 2003, 44, 5327–5330.