Practical route for N,O-heteroatom interchange in 3,5-disubstituted-4-nitroisoxazoles

Article abstract of DOI:10.1016/j.tetlet.2007.12.019

Reaction of 3-methyl-4-nitro-5-alkylisoxazoles with hydroxylamine provides a practical means to interchange the N,O-heteroatoms on the isoxazole core thereby expanding the range of compounds obtainable from 3-methyl-4-nitro-5-styrylisoxazoles.

Full text of DOI:10.1016/j.tetlet.2007.12.019

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 941–944
Practical route for N,O-heteroatom interchange
in 3,5-disubstituted-4-nitroisoxazoles
a,
b
c
c,
*
Mauro F. A. Adamo , Donato Donati , Piero Sarti-Fantoni , Arianna Buccioni
a 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
b
`
Dipartimento di Chimica, Universita di Siena, Via Aldo Moro, Siena 53100, Italy
`
Dipartimento di Chimica Organica ‘U. Schiff’, Universita di Firenze, Via della Lastruccia, Sesto Fiorentino 50019, Italy
c
Received 12 October 2007; revised 23 November 2007; accepted 5 December 2007
Available online 8 December 2007
Abstract
Reaction of 3-methyl-4-nitro-5-alkylisoxazoles with hydroxylamine provides a practical means to interchange the N,O-heteroatoms
on the isoxazole core thereby expanding the range of compounds obtainable from 3-methyl-4-nitro-5-styrylisoxazoles.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Polyfunctional scaffolds; 4-Nitroisoxazole; Heteroatom interchange
1. Introduction
NO2
NO2
O
N
N
3-Methyl-4-nitro-5-styrylisoxazoles 1 represent a class of
synthons that have been used for the preparation of several
classes of compounds.1–7 For example, we have shown that
1 could be employed for the preparation of spiroisoxazo-
lines,1,2 heteroarylpropionic acids,3–5 3-indolepropionic
acids6 and 3-arylglutaric acids.7 Compounds 1 are easily
accessible from the condensation of isoxazole 2 and an aro-
matic aldehyde 3, which are commercially available materi-
als (Fig. 1).
Ar
O
O
Ar
1
2
3
Fig. 1. Polyfunctional scaffold 5-styryl-4-nitroisoxazoles 1.
NO2
NO2
NH2NH2
N
N
N
O
H
As a part of our studies regarding the applications of 1
in synthesis (Scheme 1) we have revisited4,5 a practical
method to convert 4-nitroisoxazoles 4 into 4-nitropyrazoles
5.8 In this reaction, hydrazine attacks C-5 of the isoxazole,
which is electrophilic by conjugation to the nitro group in
C-4. This procedure involved refluxing 4-nitroisoxazoles 4
with a small excess of hydrazine (1.1 equiv) and furnished
quantitative yields of 4-nitropyrazoles 5.
Ar
R
Ar
R
4
5
R = -COOH; -CH2COOH
Ar = Ph, p-(OCH3)C6H4, p-Cl-C6H4
Scheme 1. Conversion of 4-nitroisoxazoles into 4-nitropyrazoles.
Considering that hydroxylamine behaves primarily as an
N-nucleophile, we speculated that its reaction with 3-
methyl-4-nitroisoxazoles 6 would result in the formation
of new regioisomeric isoxazoles 7. This operation consists
of a formal transposition of the C-3 and C-5 substituents
(Scheme 2). The novel 5-methyl-4-nitroisoxazoles 7 could
*
Corresponding author. Tel.: +353 1 4022208; fax: +353 1 4022168.
E-mail address: madamo@rcsi.ie (M. F. A. Adamo).
Present address: Dipartimento di Scienze Zootecniche, Universita’ di
Firenze, Via delle Cascine 5, 50144 Firenze, Italy.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.019

942
Mauro F. A. Adamo et al. / Tetrahedron Letters 49 (2008) 941–944
the crude reaction mixture showed the presence of starting
NO
R
NO
R
2
2
NH OH
2
material 8 together with a new product in a 2:3 ratio. The
new product was isolated in 55% yield using preparative
TLC and characterised as the 5-methyl-4-nitroisoxazole
9. Diagnostic for the assignment of compound 9 was the
chemical shift of the C-5 methyl, which appeared at
N
N
O
O
7
6
Scheme 2. A plan for heteroatom interchange in 4-nitroisoxazoles.
1
2.77 ppm in the H NMR spectrum.
To explore the scope of this reaction, other isoxazoles
were reacted under the same conditions (Table 1). Reaction
of compounds 8, 10, 12 and 14 with 2 equiv of hydroxyl-
amine hydrochloride and base furnished the isomeric isox-
azoles 9, 11, 13 and 15 in good yields.
then be employed as starting materials in analogy to isox-
azole 2.
2. Results and discussion
The following mechanism is proposed to explain the
conversion of 8, 10, 12 and 14 to the corresponding 9,
11, 13 and 15 (Scheme 4). Preliminary addition of hydroxyl-
Firstly, we reacted compound 85 with 2 equiv of hydrox-
ylamine hydrochloride and a base (Scheme 3). Analysis of
NO2
NO2
N
O
O
NH2OH·HCl (2 equiv)
Na2CO3 10H2O (1 equiv)
N
+ 8
C6H4pCl
CO2Et
C6H4pCl
CO2Et
EtO2C
EtO2C
55% yield
9
8
Scheme 3. Conversion of a 3-methyl-4-nitroisoxazole into a 5-methyl-4-nitroisoxazole.
Table 1
Conversion of 3-methylisoxazoles into 5-methylisoxazoles
Entry
Reactant
NO2
Product
Reactant:product in crude
Yield % of product
NO
2
O
N
1
N
2:3
55
O
C H pCl
C6H4pCl
6
4
EtO C
EtO2C
2
CO2Et
CO Et
2
8
9
NO2
NO2
N
O
N
O
2
3
4
2:3
2:3
2:3
45
49
51
tBuCO2
tBuCO2
C6H4pCl
C6H4pCl
t
t
CO2 Bu
CO2 Bu
10
11
NO
NO
2
2
N
O
O
N
C H pCl
C H pCl
6 4
6
4
13
NO
NO
12
2
2
NO2
NO
2
N
O
O
N
C H pCl
C6H4pCl
COOH
6
4
COOH
14
15

Mauro F. A. Adamo et al. / Tetrahedron Letters 49 (2008) 941–944
943
_
O
+
_
O
+
O
+
_
_
_
O
N
N
O
O
N
N
N
R
R
N
. .
HO
O
O
_
HO
R
17
N
NHOH
16
6
. .
NH OH
2
_
_
O
N
O
_
_
O
O
N
O
+
_
+
+
O
N
+
N
O
O
HOHN
O
+
HO
O
R
NH
. .
HO
R
NH
. .
HO
N
-NH OH
R
2
N
HO
R
N
N
19
18
7
Scheme 4. Proposed mechanism for the conversion of isoxazole 6 into 7.
amine to isoxazole 6 would give 16 that would ring open to
produce 17. Subsequent rearrangement of 17 would give
the stabilised iminium 18, which could undergo an intra-
molecular cyclisation to furnish 19. Finally, elimination
of hydroxylamine from 19 would give inverted isoxazole 7.
As would be expected on the basis of this mechanism, in
which each step is an equilibrium, when compound 9 was
reacted with hydroxylamine, a mixture of regioisomeric
compounds 8 and 9 was obtained in the same 2:3 ratio
(Scheme 2). Compound 9 is the major component due to
its higher acidity compared to 8, thus more of the anion
of 9 is present in the basic media.
pClC H
6
4
NO
2
8 + 9
or
10 + 11
pClC H CHO (1.0 equiv)
6 4
O
N
Piperidine (0.3 equiv)
Ethanol
C H pCl
6
4
RO C
2
CO R
2
R = Et 21 51% yield
R = Bu 22 48% yield
t
Scheme 6. Preparation of 5-styrylisoxazoles 21 and 22.
We envisaged a general strategy to prepare complex
isoxazoles 20 from starting material 2 (Scheme 5). This
plan involved a preliminary elaboration of the C-5 methyl
to generate 6 followed by interchange of 6 to 7 and a final
elaboration of 7 to 20. Considering the versatility of 5-
methyl-4-nitroisoxazoles1–7 this strategy paves the way to
the preparation of several complex isoxazoles in a regio-
controlled fashion. Thus the reactivity of the new isoxa-
In conclusion, we have identified a simple strategy that
has allowed an efficient construction of C-3 and C-5 sub-
stituents on 4-nitroisoxazoles. This methodology expands
the range of products that can be obtained from 3,5-
dimethyl-4-nitroisoxazole 2 and sets a general strategy for
the preparation of complex isoxazoles using cheap and
commercially available materials.
zoles
9
and 11 was examined by treating the
3. General procedure for the preparation of compounds 9, 11,
13 and 15 (Table 1)
regioisomeric mixtures 8+9 and 10+11 with p-chloro-
benzaldehyde and base (Scheme 6). In both cases 5-styrylis-
oxazoles 21 and 22 were obtained in good yields together
with unreacted 8 and 10.
A solution of hydroxylamine hydrochloride (0.350 g,
5 mmol), Na2CO3Á10H2O (0.720 g, 2.5 mmol) in water
(5 mL) was added to a solution of 8, 10, 12 or 14 (2.4 mmol)
in ethanol (10 mL). The reaction mixture was heated at
reflux for 4 h, then allowed to reach room temperature,
concentrated in vacuo and finally treated with dilute HCl.
The colourless solid so obtained was filtered, dried, ana-
R1
NO2
NO2
R1
NO2
C-5
elaboration
3
N,O-heteroatom
interchange
N
N
N
1
O
O
5
O
lysed by H NMR and purified by preparative silica TLC
(petroleum ether/ethyl acetate, 4:1).
2
7
6
"active"
"active"
NO2
3.1. 2-[1-(4-Chloro-phenyl)-2-(5-methyl-4-nitro-isoxazol-3-
yl)-ethyl]-malonic acid diethyl ester 9
C-5
elaboration
R1
R2
N
O
20
Colourless solid, mp 83–84 °C (ethanol), mmax (film)/
cmÀ1: 1743 (s), 1613 (m), 1510 (s), 1370 (m); dH
(200 MHz, CDCl3) 7.29–7.23 (4H, m, Ar), 4.24 (2H, q,
Scheme 5. A synthetic plan to prepare complex isoxazoles 20 from
commercial isoxazole 2.

944
Mauro F. A. Adamo et al. / Tetrahedron Letters 49 (2008) 941–944
J = 7 Hz, CH2O), 4.19–4.03 (1H, m, CHAr), 3.97 (2H, q,
J = 7 Hz, CH2O), 3.79 (1H, d, J = 10 Hz, CHCO2Et),
3.45 (2H, d, J = 7 Hz, CH2), 2.77 (3H, s, CH3), 1.31 (3H,
t, J = 7 Hz, CH2CH3), 1.04 (3H, t, J = 7 Hz, CH2CH3);
dC (80 MHz) 172.0, 168.1, 167.6, 156.6, 138.2, 133.8,
129.9, 62.4, 62.1, 58.2, 42.3, 30.8, 14.5, 14.4, 14.2; Anal.
Calcd for C19H21ClN2O7: C, 53.72; H, 4.98; N, 6.60.
Found C, 53.38; H, 5.08; N, 6.27; MS (EI): m/z 424
(100%, M+).
5.12. Found C, 57.12; H, 4.39; N, 5.11; MS (EI): m/z 547
(90%, MH+).
4.2. 2-(1-(4-Chloro-phenyl)-2-{5-[2-(4-chloro-phenyl)-
vinyl]-4-nitro-isoxazol-3-yl}-ethyl)-malonic acid dibutyl
ester 22
Yellow solid, mp 185–186 °C (ethanol), mmax (film)/
cmÀ1: 1745 (s), 1726 (s), 1610 (m), 1554 (s), 1375 (m); dH
(200 MHz, CDCl3) 7.71–7.17 (10H, m, Ar and CH@CH),
3.97 (1H, m, CHAr), 3.61 (1H, d, J = 10 Hz, CHCO),
3.43 (2H, J = 7 Hz, CH2), 1.46 (9H, s, (CH3)3C), 1.20
(9H, s, (CH3)3C); dC (80 MHz) 167.3, 167.1, 157.2, 141.7,
138.6, 137.4, 133.3, 133.1, 130.3, 129.8, 129.7, 128.7,
111.6, 66.0, 64.6, 59.8, 41.9, 31.4, 28.1, 27.8; Anal. Calcd
for C30H32Cl2N2O7: C, 59.71; H, 5.34; N, 4.64. Found C,
59.78; H, 5.69; N, 4.98; MS (EI): m/z 529 (90%, M+).
4. Synthesis of compounds 21 and 22
Piperidine (25 mg, 0.3 mmol) and a 2:3 mixture of com-
pounds 8+9 or 10+11 (2 mmol) were added to a solution of
p-chlorobenzaldehyde (170 mg, 1.0 mmol) in ethanol
(20 mL). The reaction mixture was heated at reflux for
1 h, then the solvent was removed in vacuo. The crude
material so obtained was purified by flash chromatography
eluting with petroleum ether (40–70)/ethyl acetate 11:1 to
give 21 or 22 as yellow solids.
Acknowledgement
We acknowledge the PTRLI cycle III for a Grant to
M.F.A.A.
4.1. 2-(1-(4-Chloro-phenyl)-2-{5-[2-(4-chloro-phenyl)-
vinyl]-4-nitro-isoxazol-3-yl}-ethyl)-malonic acid diethyl
ester 21
References and notes
1. Adamo, M. F. A.; Chimichi, S.; De Sio, F.; Donati, D.; Sarti-Fantoni,
P. Tetrahedron Lett. 2002, 43, 4157–4160.
2. Adamo, M. F. A.; Donati, D.; Duffy, E. F.; Sarti-Fantoni, P. J. Org.
Chem. 2005, 70, 8395–8399.
3. Adamo, M. F. A.; Duffy, E. F. Org. Lett. 2006, 8, 5157–5159.
4. Adamo, M. F. A.; Duffy, E. F.; Donati, D.; Sarti-Fantoni, P.
Tetrahedron 2007, 63, 2047–2052.
5. Adamo, M. F. A.; Duffy, E. F.; Donati, D.; Sarti-Fantoni, P.
Tetrahedron 2007, 63, 2684–2688.
Yellow solid, mp 130–131 °C (ethanol), mmax (film)/
cmÀ1: 1751 (s), 1718 (s), 1628 (m), 1556 (s), 1365 (m); dH
(200 MHz, CDCl3) 7.69–7.23 (10H, m, Ar and CH@CH),
4.29 (2H, q, J = 7 Hz, CH2O), 4.11 (1H, m, CHAr), 4.02
(2H, q, J = 7 Hz, CH2O), 3.86 (1H, d, J = 10 Hz, CHCO),
3.53 (2H, J = 7 Hz, CH2), 1.36 (3H, t, J = 7 Hz, CH2CH3),
1.05 (3H, t, J = 7 Hz, CH2CH3); dC (80 MHz) 168.1, 167.6,
167.5, 157.2, 147.2, 138.3, 137.8, 133.7, 133.2, 130.2, 130.0,
129.9, 129.1, 111.7, 62.5, 62.0, 58.3, 42.4, 31.0, 14.6, 14.2;
Anal. Calcd for C26H24Cl2N2O7: C, 57.05; H, 4.42; N,
6. Adamo, M. F. A.; Konda, V. R. Org. Lett. 2007, 9, 303–305.
7. Adamo, M. F. A.; Konda, V. R.; Donati, D.; Sarti-Fantoni, P.;
Torroba, T. Tetrahedron 2007, 63, 9741–9745.
8. Musante, C. Gazz. Chim. Ital. 1942, 72, 537–542.