One-step synthesis of differently bis-functionalized isoxazoles by cycloaddition of carbamoylnitrile oxide with β-keto esters

Article abstract of DOI:10.1039/c2ob06925c

A new protocol for synthesizing different functionalized isoxazoles is provided. Carbamoylnitrile oxide generated from nitroisoxazolone underwent inverse electron-demand 1,3-dipolar cycloaddition with 1,3-dicarbonyl compounds in the presence of magnesium

Full text of DOI:10.1039/c2ob06925c

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PAPER
One-step synthesis of differently bis-functionalized isoxazoles by
cycloaddition of carbamoylnitrile oxide with β-keto esters†
Nagatoshi Nishiwaki,*a Kazuya Kobiro,a Shotaro Hirao,a Jun Sawayama,a Kazuhiko Saigo,a Yumiko Ise,b
Maho Nishizawab and Masahiro Arigab
Received 15th November 2011, Accepted 19th December 2011
DOI: 10.1039/c2ob06925c
A new protocol for synthesizing different functionalized isoxazoles is provided. Carbamoylnitrile oxide
generated from nitroisoxazolone underwent inverse electron-demand 1,3-dipolar cycloaddition with
1,3-dicarbonyl compounds in the presence of magnesium acetate that formed magnesium enolate in situ.
Although electron-deficient trifluoroacetoacetate did not undergo this cycloaddition under the same
conditions, conversion to sodium enolate furnish the corresponding bis-functionalized
trifluoromethylisoxazole. The DFT calculations using B3LYP 6-31G+(d,p) also supported the
aforementioned reactivity.
Introduction
Functional groups on heterocyclic frameworks serve as scaffolds
for further chemical transformation for the development of func-
tional materials such as medicines, dyes, agrochemicals, and
optical materials. Heterocyclic systems with multiple functional
groups are synthetic intermediates of great importance; however,
it is often difficult to introduce more than two different func-
tional groups onto a heterocyclic framework. Because of the
increasing demand, the development of a new functionalized
building block is highly desired.
1,3-Dipolar cycloaddition has been employed as a powerful
synthetic procedure by which five-membered heterocyclic frame-
Scheme 1 Cycloaddition of nitrile oxide 2 with alkene leading to iso-
xazoline 3 and ring transformation of nitroisoxazolone 1 with sodium
enolate 4a leading to pyrrole 6.
works are constructed together with forming two bonds in a
single manipulation.1 In particular, 1,3-dipoles having a func-
tional group serve as useful building blocks for obtaining func-
tionalized heterocyclic compounds. Recently, we demonstrated a
generation method for generating carbamoylnitrile oxide 2 by
sodium enolate of ethyl acetoacetate 4a (Scheme 1).5 In this
reaction, a trace amount of bis-functionalized isoxazole 5a was
isolated as a by-product, which indicated that enolate 4a or its
protonated form, ethyl acetoacetate 7a, served as a dipolarophile.
Indeed, the same product 5a was prepared with a 41% yield by
the cycloaddition of 2 with enamine 8a,6 which was easily pre-
pared by heating ethyl acetoacetate 7a with pyrrolidine without
solvent (Scheme 2). These experimental facts prompted us to
study direct syntheses of differently bis-functionalized isoxazoles
by cycloaddition of 2 with β-keto esters.
treating nitroisoxazolone 1 with just water under mild con-
ditions,2 which underwent cycloadditions with alkynes, alkenes,
and nitriles to afford carbamoyl-substituted isoxazoles,2 isoxazo-
lines 3 (Scheme 1),2,3 and 1,2,4-oxadiazoles,4 respectively. We
also demonstrated a preparative method for 1,2-dimethyl-3-
ethoxycarbonyl-4-nitropyrrole (6) from nitroisoxazolone 1 and
aSchool of Environmental Science and Engineering, Kochi University
of Technology, Tosayamada Kami, Kochi 782-8502, Japan.
E-mail: nishiwaki.nagatoshi@kochi-tech.ac.jp; Fax: +81 887 57 2520;
Tel: +81 887 57 2517
Results and discussion
bDepartment of Chemistry, Osaka Kyoiku University, Asahigaoka,
Kashiwara, Osaka 582-8582, Japan
Among the numerous studies on nitrile oxides, only those
examples, in which a 1,3-dicarbonyl compound was employed
as a dipolarophile are found in the literature (Scheme 3).
†Electronic supplementary information (ESI) available: Experimental
procedures and spectral data of cycloadducts 5a–h and magnesium
enolate 9a. See DOI: 10.1039/c2ob06925c
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Table 1 Calculated HOMO–LUMO energy gaps (eV) using DFT
method
Nitrile Oxide
2
9
10
H
Dipolarophile
Ha
L
H
L
L
Scheme 2 Cycloaddition using enamine 8a.
4a
4b
7a
7b
H
L
H
L
H
L
H
L
—
10.77
—
10.90
—
6.49
—
6.03
0.75
—
0.73
—
5.13
—
5.17
—
—
11.08
—
11.20
—
6.79
—
6.33
1.29
—
1.28
—
4.58
—
4.63
—
—
9.82
—
5.73
—
5.54
—
5.08
4.85
—
4.98
—
5.10
—
5.14
—
a H: HOMO, L: LUMO.
In order to realize the aforementioned reactivities, the HOMO/
LUMO energy gaps between nitrile oxides 2, 9, 10 and enolates
4a,b or enols 11a,b were estimated by DFT methods using
B3LYP 6-31G+(d,p) in advance (Table 1). In the cycloadditions
of phenylnitrile oxide 10 (Ar = Ph) with 1,3-dicarbonyl com-
pounds 11a,b, the conversion of dipolarophiles to the corre-
sponding enolates 4a,b seems to be somewhat advantageous.
To the contrary, nitrile oxides 2 and 9 having an electron-
withdrawing group are considerably effective and the cyclo-
additions with enolates 4a,b are predicted to proceed with high
efficiency. In particular, carbamoylnitrile oxide 2 is expected to
reveal higher reactivity than ethoxycarbonylnitrile oxide 9.
These encouraging results indicated that enolates of less reactive
β-keto esters surely serves as the dipolarophile if nitrile oxide 2
is employed.
Initially, we employed THF as a solvent, because it was found
to be superior from the viewpoint of the reactivity control to the
mixture of water and acetonitrile reported in our previous
work.2,4 However, no reaction of nitroisoxazolone 1 was
observed even after heating 1 with ethyl acetoacetate 7a under
reflux in THF for 1 d (Table 2, run 1). Therefore, copper acetate
was added in anticipation of fixing 7a to an enol form by chela-
tion or forming metal enolate 9. In contrast to the result of run 1,
the addition of 0.5 equivalent of copper acetate was effective in
promoting the cycloaddition with 2 under the same conditions
leading to desired isoxazole 5a with a 33% yield (run 2). The
amount of 7a was found to be an influential factor, and the
employment of 5 equivalents of 7a increased the yield of 5a to
67% (runs 2–5). Dried copper acetate revealed the same reactiv-
ity as the hydrated form (runs 4 and 6), which means the cyclo-
addition proceeded irrespective of the presence of water. This
successful result prompted us to search for a more effective
metal salt. Several commonly used several transition metal acet-
ates exhibited similar chelation effects (runs 7–10). Intriguingly,
environmentally benign magnesium salts also served as activat-
ing agents to promote the cycloaddition (runs 11–15). Among
several salts, magnesium acetate was found to be the most
efficient promoter affording isoxazole 5a with an 80% yield
(run 11).
Scheme 3 Other cycloadditions of nitrile oxides with 1,3-dicarbonyl
compounds.
Umesha et al. prepared 4-acetyl-3-arylisoxazoles by the cyclo-
addition of isolable aromatic nitrile oxides with acetylacetone
7b.7 Suzuki and co-workers developed the cyclocondensation of
hindered aromatic nitrile oxides with cyclic β-diketones, which
was applied to the synthesis of natural products.8 In these reac-
tions, nitrile oxide was stable enough for isolation; thus a substi-
tuent at the 3-position of the cycloadducts was limited to an
aromatic group.
On the other hand, a nitrile oxide 9 possessing an electron-
withdrawing ester function is also usable for the cycloaddition
with β-diketones to afford 3,4-bis(functionalized) isoxazoles, in
which the diketone is converted to an electron-rich sodium
enolate 4b.9 Recently, Trogu et al. synthesized a similar frame-
work by the copper catalyzed cycloaddition/condensation of
β-diketones with several functionalized nitrile oxides derived
from α-nitrated carbonyl compounds.10 In contrast to these suc-
cessful studies using β-diketones, less reactive β-keto esters have
not been employed as dipolarophiles for nitrile oxide cycloaddi-
tions except for a few examples that suffer from limited scope11
and low yields.10,12 These facts and our experimental results
strongly encouraged us to study the cycloaddition of carbamoyl
nitrile oxide 2 with β-keto esters as well as β-diketones.
1
The role of magnesium acetate was monitored by H NMR.
The spectrum of ethyl acetoacetate 7a in THF-d8 revealed
signals of both keto and enol forms in an 85 : 15 ratio. When the
1988 | Org. Biomol. Chem., 2012, 10, 1987–1991
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Table 2 Optimization of reaction conditions for cycloaddition of
nitrile oxide 2 with 7a
Run
7a(equiv.)
Additive
Yield of 5a (%)
1
2
3
4
5
6
7
8
0
1
3
5
7
5
5
5
5
5
5
5
5
5
5
None
0
33
51
67
64
66
54
59
49
59
80
50
31
30
0
Cu(OAc)2 ˙ H2O
Cu(OAc)2 ˙ H2O
Cu(OAc)2 ˙ H2O
Cu(OAc)2 ˙ H2O
Cu(OAc)2
Mn(OAc)2 ˙ 4H2O
Co(OAc)2 ˙ 4H2O
Ni(OAc)2 ˙ 4H2O
Zn(OAc)2 ˙ 2H2O
Mg(OAc)2 ˙ 4H2O
Mg(ClO4)2
9
10
11
12
13
14
15
Scheme 4 Cycloaddition with keto ester 7a.
MgCl2
MgO
MgSO4
Table 3 Cycloaddition using other 1,3-dicarbonyl compounds
Run
R1
R2
Yield (%)
1
2
3
4
5
6
7
8
9
OEt
Me
Ph/Me
OMe
OEt
OMe
OEt
Me
Me
Me/Ph
Et
Ph
CH2OMe
CH2COOEt
CF3
a
80
quant.
96 (67/29)
88
96
60
59
0
b
c/c′
d
e
f
g
OEt
OEt
h
j
OEt
0
Fig. 1 1H NMR spectrum after heating 7a with Mg(OAc)2 for 1 d in
THF-d8.
The cycloaddition of nitrile oxide 2 also proceeded to afford
polyfunctionalized isoxazoles 7f and 7g, even though an elec-
tron-withdrawing group was substituted at the keto moiety (runs
6 and 7). However, trifluoroacetoacetate 7h did not undergo any
change under the present conditions (run 8). When an α-substi-
tuted β-keto ester, α-methylacetoacetate 7i, was employed, a
complex mixture was formed without detectable tetrasubstituted
isoxazoline, in which furoxan 10 was the main product (56%
yield) as a result of the self-cycloaddition of nitrile oxide 2
(Fig. 2). While keto esters served well as dipolarophiles, diester
7j was inactive and was recovered under the same conditions.
As mentioned above, highly electron-deficient keto ester 7h
was an inactive dipolarophile. This disadvantage was overcome
by converting keto ester 7h to electron-rich sodium enolate 4h
beforehand, which underwent an inverse electron-demand 1,3-
dipolar cycloaddition4 with nitrile oxide 2 even at room tempera-
ture leading to 5-trifluoromethylisoxazole 5h with 57% yield
(Scheme 5).
solution of 7a was heated at 70 °C for 1 d in the presence of
magnesium acetate, minor signals were observed in addition to
the above-mentioned signals as indicated in Fig. 1 (detailed
spectra are shown in the Supporting Information†). Since the
electron density of the newly formed species is higher than that
of 7a, magnesium enolate 9a possibly forms in situ and serves
as an electron-rich dipolarophile for the present cycloaddition
(Scheme 4).
Acetylacetone 7b exhibited higher reactivity than keto ester
7a to afford cycloadduct 5b10 quantitatively (Table 3, run 2). In
the case of benzoylacetone 7c, the formation of the two regioi-
somers 5c and 5c′13 was possible, of which 4-benzoyl derivative
5c was formed in preference to 4-acetyl one 5c′ (run 3). Other
β-keto esters 7d–i were subjected to the present cycloaddition
under the same conditions (runs 4–8). As a result, it was possible
to introduce an ethyl or phenyl group at the 5-position by the
use of the corresponding keto esters 7d and 7e (runs 4 and 5).
Isoxazoles having vicinal functionalities at the 3- and 4-pos-
itions are important scaffolds for developing medicines14 and
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(108 mg, 0.5 mmol), and the resultant mixture was heated under
reflux for 1 d. After addition of 1 M hydrochloric acid (10 mL,
10 mmol), THF was removed under reduced pressure. The resul-
tant aqueous solution was extracted with chloroform (50 mL ×
5), and the organic layer was dried over magnesium sulfate, and
concentrated. The residue was subjected to column chromato-
graphy on silica gel to afford cycloadduct 5a (170 mg,
0.80 mmol, 80%) eluted with ethyl acetate. Further purification
was performed by recrystallization from a mixed solvent of
hexane and benzene (1 : 1).
Fig. 2 Magnesium acetate 9a, α-methylacetoacetate 7i, and furoxan
10.
Cycloadditions of 1 with other 1,3-dicarbonyl compounds
5b–j were conducted in the same way.
4-Ethoxycarbonyl-5-methyl-3-(N-methylcarbamoyl)isoxazole
(5a). Colorless needles (from benzene/hexane = 1 : 1). Mp
1
55–58 °C. IR (KBr) 3271, 1721, 1663 cm−1; H NMR (CDCl3)
δ 1.38 (t, J = 7.1 Hz, 3H), 2.70 (s, 3H), 3.00 (d, J = 4.8 Hz, 3H),
4.37 (q, J = 7.1 Hz, 2H), 8.2-8.4 (br, 1H); 13C NMR (CDCl3) δ
13.8 (CH3), 14.1 (CH3), 26.5 (CH3), 61.9 (CH2), 108.0 (C),
157.3 (C), 158.9 (C), 162.5 (C), 176.3 (C); MS (FAB) m/z = 213
(M+ + 1, 100%). Anal. Calcd for C9H12N2O4: C, 50.94; H, 5.70;
N, 13.20. Found: C, 50.64; H, 5.88; N, 13.17.
Scheme 5 Synthesis of 5-trifluoromethylisoxazole 5h.
agrochemicals;15 however, multi-step processes are often necess-
ary for their synthesis. In contrast, our protocol using a
1,3-dipolar cycloaddition realizes an easier access to these frame-
works. The present reaction does not require troublesome manip-
ulations, environmentally hazardous reagents, or severe reaction
conditions. Hence, this protocol will be a practical and useful
tool in organic syntheses.
4-Benzoyl-5-methyl-3-(N-methylcarbamoyl)isoxazole (5c).
Yellow oil. IR (KBr) 3357, 1672, 1649 cm−1; 1H NMR (CDCl3)
δ 2.44 (s, 3H), 2.90 (d, J = 5.0 Hz, 3H), 6.9-7.0 (br, 1H), 7.47
(dd, J = 8.4, 7.5 Hz, 2H), 7.55 (dt, J = 7.5, 1.2 Hz, 1H), 7.78
(dd, J = 8.4, 1.2 Hz, 2H); 13C NMR (CDCl3) δ 12.4 (CH3), 26.3
(CH3), 115.9 (C), 128.7 (CH), 129.2 (CH), 133.8 (CH), 137.5
(C), 157.2 (C), 158.6 (C), 172.2 (C), 189.1 (C); MS (FAB) m/z
= 245 (M+ + 1, 100%), 105 (40). Anal. Calcd for C13H12N2O3:
C, 63.93; H, 4.95; N, 11.47. Found: C, 63.91; H, 4.78; N, 11.35.
Experimental
General
The melting points were determined on a Yanaco micro-melting-
point apparatus, and were uncorrected. All the reagents and sol-
vents were commercially available and used as received. The H
4-Acetyl-3-(N-methylcarbamoyl)-5-phenylisoxazole (5c′). Col-
orless needles (from benzene/hexane = 1 : 1). Mp 155–159 °C.
1
1
IR (KBr) 3321, 1706, 1662 cm−1; H NMR (CDCl3) δ 2.57 (s,
NMR spectra were measured on a Bruker DPX-400 at 400 MHz
with TMS as an internal standard. The 13C NMR spectra were
measured on a Bruker DPX-400 at 100 MHz, and assignments
of 13C NMR spectra were performed by DEPT experiments. The
IR spectra were recorded on a Horiba FT-200 IR spectrometer.
The mass spectra were recorded on a JEOL JMS-AX505HA a
mass spectrometer. The high resolution mass spectra were
measured on a JEOL JMS-DX303HF. The elemental microana-
lyses were performed using a Yanaco MT-3 CHN recorder.
3H), 3.04 (d, J = 5.0 Hz, 3H), 6.9-7.0 (br, 1H), 7.45-7.55 (m,
3H), 7.73 (dd, J = 8.3, 1.2 Hz, 2H); 13C NMR (CDCl3) δ 26.3
(CH3), 32.0 (CH3), 117.3 (C), 126.1 (C), 127.7 (CH), 129.1
(CH), 131.5 (CH), 156.6 (C), 159.0 (C), 169.0 (C), 196.0 (C);
MS (FAB) m/z = 245 (M+ + 1, 100%). Anal. Calcd for
C13H12N2O3: C, 63.93; H, 4.95; N, 11.47. Found: C, 64.12; H,
4.95; N, 11.45.
5-Ethyl-4-methoxycarbonyl-3-(N-methylcarbamoyl)isoxazole
(5d). Colorless needles (from benzene/hexane = 1 : 1). Mp
86–88 °C. IR (Nujol) 3273, 1713, 1670 cm−1 1H NMR
;
2-Methyl-4-nitro-3-isoxazolin-5(2H)-one (2)2
(CDCl3) δ 1.34 (t, J = 7.6 Hz, 3H), 3.03 (d, J = 4.9 Hz, 3H),
3.10 (q, J = 7.6 Hz, 2H), 3.91 (br, 1H), 7.6-7.8 (br, 1H); 13C
NMR (CDCl3) δ 11.5 (CH3), 21.3 (CH2), 26.5 (CH3), 52.6
(CH3), 107.1 (C), 157.3 (C), 158.1 (C), 162.7 (C), 180.6 (C);
MS (FAB) m/z = 213 (M+ + 1, 100%). Anal. Calcd for
C9H12N2O4: C, 50.94; H, 5.70; N, 13.20. Found: C, 50.88; H,
5.94; N, 13.14.
Nitroisoxazolone 2 was easily prepared from commercially avail-
able ethyl nitroacetate through three steps with simple exper-
imental manipulations; 1) the condensation of nitroacetate with
orthoformate, 2) the condensation with hydroxylamine, and 3)
the N-methylation with dimethyl sulfate (Details are given in
Supporting Information†).
4-Ethoxycarbonyl-3-(N-methylcarbamoyl)-5-phenylisoxazole
(5e). Colorless needles (from benzene/hexane = 1 : 1). Mp
Cycloaddition of nitrile oxide with dipolarophiles
113–116 °C. IR (KBr) 3299, 1726, 1664 cm−1 1H NMR
;
General procedure. To a solution of nitroisoxazolone 1
(144 mg, 1 mmol) in THF (10 mL), were added ethyl acetoace-
tate 7a (0.63 mL, 5 mmol) and magnesium acetate tetrahydrate
(CDCl3) δ 1.31 (t, J = 7.1 Hz, 3H), 3.03 (d, J = 4.8 Hz, 3H),
4.36 (q, J = 7.1 Hz, 2H), 7.1-7.3 (br, 1H), 7.45-7.60 (m, 3H),
7.84 (dd, J = 8.4, 1.1 Hz, 2H); 13C NMR (CDCl3) δ 13.8 (CH3),
1990 | Org. Biomol. Chem., 2012, 10, 1987–1991
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26.4 (CH3), 61.2 (CH2), 108.0 (C), 126.1 (C), 128.2 (CH), 128.8
(CH), 131.6 (CH), 157.8 (C), 158.9 (C), 162.1 (C), 171.4 (C);
MS (FAB) m/z = 275 (M+ + 1, 100%). Anal. Calcd for
C14H14N2O4: C, 61.31; H, 5.15; N, 10.21. Found: C, 61.38; H,
5.30; N, 10.21.
13.6 (CH3), 26.5 (CH3), 63.2 (CH2), 113.5 (C), 117.1 (q, JC-F
271 Hz, CF3), 157.1 (C), 157.35 (C), 158.8 (C), 159.0 (q, JC-F
=
=
41 Hz, C
̲
Calcd for C9H9N2O4F3: C, 40.61; H, 3.41; N, 10.52. Found: C,
40.80; H, 3.36; N, 10.63.
4-Methoxycarbonyl-5-methoxymethyl-3-(N-methylcarbamoyl)
isoxazole (5f). Colorless needles (from benzene/hexane = 1 : 1).
Mp 40–44 °C. IR (KBr) 3267, 1723, 1671 cm−1 1H NMR
;
Notes and references
(CDCl3) δ 3.02 (d, J = 4.9 Hz, 3H), 3.49 (s, 3H), 3.92 (s, 3H),
4.82 (s, 2H), 7.7-7.8 (br, 1H); 13C NMR (CDCl3) δ 26.5 (CH3),
52.9 (CH3), 59.5 (CH3), 64.9 (CH2), 109.3 (C), 157.3 (C), 158.7
(C), 161.9 (C), 174.2 (C); MS (FAB) m/z = 229 (M+ + 1, 100%).
Anal. Calcd for C9H12N2O5: C, 47.37; H, 5.30; N, 12.28.
Found: C, 47.01; H, 5.67; N, 12.42.
1 A. Padwa, W. H. Pearson, E. C. Taylor and P. Wipf, Synthetic Application
of 1,3-Dipolar Cycloaddition Chemistry toward Heterocycles and
Natural Products, Wiley–Interscience, New York, (2002).
2 N. Nishiwaki, K. Kobiro, H. Kiyoto, S. Hirao, J. Sawayama, K. Saigo,
Y. Okajima, T. Uehara, A. Maki and M. Ariga, Org. Biomol. Chem.,
2011, 9, 2832; N. Nishiwaki, T. Uehara, N. Asaka, Y. Tohda, M. Ariga
and S. Kanemasa, Tetrahedron Lett., 1998, 39, 4851.
3 N. Nishiwaki, A. Maki and M. Ariga, J. Oleo Sci., 2009, 58, 481.
4 N. Nishiwaki, K. Kobiro, S. Hirao, J. Sawayama, K. Saigo, Y. Ise,
Y. Okajima and M. Ariga, Org. Biomol. Chem., 2011, 9, 6750.
5 N. Nishiwaki, M. Nakanishi, T. Hida, Y. Miwa, M. Tamura, K. Hori,
Y. Tohda and M. Ariga, J. Org. Chem., 2001, 66, 7535.
4-Ethoxycarbonyl-5-ethoxycarbonylmethyl-3-(N-methylcarba-
moyl)isoxazole (5g). Brown oil. IR (KBr) 3303, 1739,
1
1674 cm−1; H NMR (CDCl3) δ 1.26 (t, J = 7.1 Hz, 3H), 1.36
(t, J = 7.1 Hz, 3H), 3.02 (d, J = 5.0 Hz, 3H), 4.13 (s, 2H), 4.20
(q, J = 7.1 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 8.2-8.4 (br, 1H);
13C NMR (CDCl3) δ 13.9 (CH3), 14.1 (CH3), 26.5 (CH3), 33.9
(CH2), 62.1 (CH2), 109.7 (C), 157.3 (C), 158.5 (C), 161.8 (C),
166.3 (C), 171.8 (C); MS (FAB) m/z = 285 (M+ + 1, 100%).
Anal. Calcd for C12H16N2O6: C, 50.70; H, 5.67; N, 9.85. Found:
C, 50.54; H, 5.85; N, 9.63.
6 Cycloadditions of nitrile oxide with enamino esters: S. Zhu, S. Shi and
S. W. Gerritz, Tetrahedron Lett., 2011, 52, 4001; G. Stork and
J. E. McMurry, J. Am. Chem. Soc., 1967, 89, 5461.
7 K. B. Umesha, K. A. Kumar and K. M. L. Rai, Synth. Commun., 2002,
32, 1841.
8 Y. Koyama, R. Yamaguchi and K. Suzuki, Angew. Chem., Int. Ed., 2008,
47, 1084; T. Matsuura, J. W. Bode, Y. Hachisu and K. Suzuki, Synlett,
2003, 1746; J. W. Bode, Y. Hachisu, T. Matsuura and K. Suzuki, Tetrahe-
dron Lett., 2003, 44, 3555.
9 I. Marchueta Hereu and X. Serra Masia, PCT Int., WO 2008 107064
(2008) D. Chiarino, G. Grancini, V. Frigeni, I. Biasini and A. Carenzi,
J. Med. Chem., 1991, 34, 600.
10 E. Trogu, L. Cecchi, F. De Sarlo, L. Guideri, F. Ponticelli and F. Machetti,
Eur. J. Org. Chem., 2009, 5971.
11 4-Methyl-3-oxopentanoic acid esters were employed as the dipolarophile:
V. Maywald, T. Kuekenhoehner, P. Muenster and S. Stahl, Eur. Pat. Appl.,
562382 (1993).
12 T. Shimizu, Y. Hayashi and K. Teramura, Bull. Chem. Soc. Jpn., 1985,
58, 2519.
Cycloaddition using sodium enolate of ethyl trifluoroacetate
4h. To a solution of ethyl trifluoroacetoacetate 7h (0.59 mL,
5 mmol) in ethanol (10 mL), sodium (115 mg, 5 mmol) was
gradually added. After stirring at room temperature for 15 min,
the mixture was dried up under reduced pressure, and then the
residue was dissolved in THF (10 mL). To the solution, a sol-
ution of nitroisoxazolone 1 (144 mg, 1 mmol) in acetonitrile
(10 mL) was added, and the resultant mixture was stirred at
room temperature for 3 d. After addition of 1 M hydrochloric
acid (10 mL, 10 mmol), solvents were removed under reduced
pressure. The resultant aqueous solution was extracted with
chloroform (50 mL × 5), and the organic layer was dried over
magnesium sulfate, and concentrated. The residue was subjected
to the column chromatography on silica gel to afford cyclo-
adduct 5h (125 mg, 0.51 mmol, 51%) eluted with ethyl acetate.
Further purification was performed by recrystallization from a
mixed solvent of hexane and benzene (1 : 1).
13 The presence of an acetyl group in 5i′ was confirmed by the iodoform
reaction.
14 For example: R. Palin, P. D. Ratcliffe, S. G. Kultgen, S. G.; K.-K. Ho,
A. L. Roughton and M. Ohlmeyer, PCT Int. Appl., WO 2010 091009
(2010); A. A. Ivashchenko, A. V. Ivaschenko, S. Y. Tkachenko,
I. M. Okun, N. F. Savchuk, D. V. Kravchenko, E. A. Rizhova,
S. B. Alyabiev and A. V. Khvat, PCT Int. Appl., WO 2009 010925
(2009); M. Takagi, T. Nakamura, I. Matsuda, T. Kiguchi, N. Ogawa and
H. Ozeki, PCT Int. Appl., WO 2008 062739 (2008); S.-I. Nishimura and
H. Kondo, PCT Int. Appl., WO 2007 081031 (2007); S. Saito, H. Ohta,
T. Ishizaka, M. Yoshinaga, M. Tatsuzuki, Y. Yokobori, Y. Tomishima,
A. Morita, Y. Toda, K. Tokugawa, A. Kaku, T. Murakami, H. Yoshimura,
S. Sekine and T. Yoshimizu, PCT Int. Appl., WO 2006 051704 (2006).
15 For example: R. L. Vozouet, S. Soergel, C. Defieber, S. Gross,
K. Koerber, D. L. Culbertson and D. D. Anspaugh, PCT Int. Appl., WO
2011 003793 (2011) C. B. Vicentini, C. Romagnoli, E. Andreotti and
D. Mares, J. Agric. Food Chem., 2007, 55, 10331; P. Muenster,
W. Freund, V. Maywald, T. Kuekenhoehner, M. Gerber, K. Grossmann
and H. Walter, Pestic. Sci., 1995, 44, 21.
4-Ethoxycarbonyl-5-trifluoromethyl-3-(N-methylcarbamoyl)
isoxazole (5h). Colorless needles (from benzene/hexane = 5 : 4).
Mp 81–83 °C. IR (KBr) 3291, 1745, 1656 cm−1 1H NMR
;
(CDCl3) δ 1.39 (t, J = 7.1 Hz, 3H), 3.04 (d, J = 5.0 Hz, 3H),
4.44 (q, J = 7.1 Hz, 2H), 7.2-7.4 (br, 1H); 13C NMR (CDCl3) δ
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