Epoxidation of 3-methyl-4-N-acetyl-5-styrylisoxazoles

Article abstract of DOI:10.1016/j.tetlet.2007.05.012

An efficient synthesis of novel isoxazoloepoxides is described. The title compounds were obtained in high yields and without the use of chromatography.

Full text of DOI:10.1016/j.tetlet.2007.05.012

Tetrahedron Letters 48 (2007) 4703–4706
Epoxidation of 3-methyl-4-N-acetyl-5-styrylisoxazoles
Mauro F. A. Adamo* and Murali Nagabelli
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
Received 24 March 2007; revised 26 April 2007; accepted 2 May 2007
Available online 10 May 2007
Abstract—An efficient synthesis of novel isoxazoloepoxides is described. The title compounds were obtained in high yields and with-
out the use of chromatography.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
As part of our ongoing studies on the generation of
chemical diversity using polyfunctional scaffolds, we
became interested in the preparation of epoxides 4
(Fig. 1). Similar to compounds 1, epoxides 4 possess
two electrophilic centres that can be reacted selectively.
Epoxides are versatile synthons that can be regio- and
stereoselectively ring opened when reacted with suitable
nucleophiles. Additionally, several methods of asymmet-
ric epoxidation of alkenes are available, which can be
used to prepare 4 in enantiopure form.16 Therefore,
compounds 4 constitute a stereospecific version of scaf-
folds 1 that we hope to employ to generate diversity in
stereoselective fashion. Considering that a 4-nitroisoxaz-
ole core represents a masked carboxylate10–15 or a pro-
tected b-diketone,1 it is easy to envisage the potential
of compounds 4 in diversity oriented syntheses.
The isoxazole nucleus has been recognised as an impor-
tant heterocycle in medicinal chemistry.1 Several reports
have appeared describing the biological activity of
isoxazoles as selective agonists of the dopamine D4
receptor,2 GABAA antagonists,3 analgesics,4 antiinflam-
matories,4 antimicrobials,5 antifungals,5 COX-2 inhibi-
tors,6 antinociceptives7 and anticancer agents.8 For
this reason the synthesis of novel compounds containing
the isoxazole core is of interest for the academic and
industrial communities.
3-Methyl-4-nitro-5-styrylisoxazoles 1 (Fig. 1) represent
a class of polyfunctional scaffolds, which hold excel-
lent potential for the generation of diversity.9–15 Our
approach to the development of multicomponent diver-
sity oriented syntheses is based on the generation of
building blocks containing several functionalities which
can be reacted selectively.9–15 For example, we have
shown that 1 could be employed efficiently for the prep-
aration of spiroisoxazolines,9,10 heteroarylpropionic
acids11–14 or 3-indolepropionic acids.15 In these synthe-
ses, the two electrophilic centres present in 1 were
reacted selectively and independently. Compounds 1
are easily accessible from the condensation of isoxazole
2 and an aromatic aldehyde 3, which are commercially
available materials.
We started our investigation with the epoxidation of
3-methyl-4-nitro-5-styrylisoxazole 1a (Scheme 1). This
was a logical starting point as compounds 1 are accessi-
ble from commercially available materials (Fig. 1).
The oxidation of 1a was attempted using several oxida-
tion methods, which included uncatalysed processes,
metal catalysed processes and organo catalytic proce-
dures. Unfortunately, the preparation of 6 proved elu-
sive. Compound 1a was reacted with tBuOOH/
Bu4NBr; H2O2 in a basic medium (Et3N or KOH); Bu4-
NIO4; m-CPBA; (Salen)RuIII/tBuOOH; (Salen)CrII/
tBuOOH; (Salen)ZnII/tBuOOH; (Salen)MnII/tBuOOH;
and dimethyldioxirane (DMD). However, compound
1a was recovered quantitatively at the end of each experi-
ment, showing a remarkable stability in the presence of
oxidants. We concluded that the resistance to oxidation
was due to conjugation of the exocyclic alkene in 1a with
Keywords: Polyfunctional scaffolds; Isoxazoloepoxides; Dioxiranes.
Corresponding author. Tel.: +353 1 4022208; fax: +353 1 4022168;
*
e-mail: madamo@rcsi.ie
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.012

4704
M. F. A. Adamo, M. Nagabelli / Tetrahedron Letters 48 (2007) 4703–4706
NO
2
EWG
N
+
+
NO
2
E
1
2
O
O
N
O
+
N
O
E
Ar
1
Ar
O
+
E
2
Ar
electrophilic
centres
E
4
1
2
3
Figure 1. Two polyfunctional scaffolds: 5-styryl-4-nitroisoxazole 1 and isoxazoloepoxides 4.
Table 1. One-pot preparation of 4a–g
NO
NO2
2
Entry
Compound
Ar
Yielda (%)
N
N
O
O
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
Ph–
86
87
76
81
63
72
79
O
X
p-CH3–C6H4
p-CH3O–C6H4
p-Cl–C6H4
p-(NHCOCH3)–C6H4
3,4-CH3O–C6H3
2,4,6-CH3–C6H2
1a
6
Scheme 1. Epoxidation of 3-methyl-4-nitro-5-styrylisoxazole.
4g
a Isolated yield after work up.
the nitro group. Therefore, it was decided to replace the
nitro group with a milder electron withdrawing group.
In our plan an electron withdrawing group was required
to maintain C-5 of the isoxazole (Eþ1 Þ activated towards
nucleophilic addition. The N-acetoxy group was selected
considering its ease of preparation from isoxazoles 1a–g.
detrimental to the epoxidation yield (Scheme 3 and
Table 2).
Given the presence of several functionalities in com-
pounds 5a–g, they constitute a class of ideal starting
materials for further synthetic transformations. For
example, the epoxide can be ring opened by a variety
of nucleophiles and once the epoxide is reacted, the isox-
azole ring could be elaborated to an isoxazoline, a
carboxylate, a polyaminoalcohol, or an eneaminone.
In conclusion, we have developed a synthetic method
to prepare compounds 5a–g, which were obtained in
high yields and without the use of chromatography.
Studies on the asymmetric epoxidation of 5a–g and their
Compounds 1a–g were submitted to reduction using
SnCl2, and amines 3a–g were obtained in good yields.
Subsequent acetylation of the amino group in 3a–g fur-
nished the desired N-acetylisoxazoles 4a–g. These two
steps could be performed in one-pot and 4a–g were ob-
tained without the need for isolating 3a–g (Scheme 2,
Table 1). Compounds 4a–g were reacted with Oxoneꢁ
and acetone, a standard procedure to generate di-
methyldioxirane in situ.16 We were delighted to observe
that under these conditions, epoxidation of 4a–g affor-
ded 5a–g in high yields (Table 2). Compounds 5a–g were
obtained sufficiently pure to be carried to the next trans-
formation without the use of chromatography. We have
also shown that synthons 5a–g could be prepared from
1a–g without purification of intermediates 3a–g and
4a–g (Scheme 3).
Table 2. Preparation of isoxazoloepoxides 5a–g
Entry
Compound
Ar
Yielda (%)
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
Ph–
95
84
86
82
78
81
82
p-CH3–C6H4
p-CH3O–C6H4
p-Cl–C6H4
p-(NHCOCH3)–C6H4
3,4-CH3O–C6H3
2,4,6-CH3–C6H2
This rendered the synthesis of epoxides 5a–g operation-
ally simple. The electronic nature of the substituent on
the aromatic group could be varied to include electron
releasing and withdrawing groups without this being
5g
a Isolated yield after work up.
NHCOCH
3
NH
NO
2
2
N
N
AcCl, TEA, CH2Cl2
N
SnCl2 / HCl
O
O
O
THF, 20 oC, 2 h
0 oC to 20 oC, 30 min
1a-g
3a-g
4a-g
Ar
Ar
Ar
o
o
o
1. SnCl / HCl/THF, 25 C, 2 h; 2. AcCl, TEA, CH Cl , 0 C to 20 C, 30 min
2
2
2
Scheme 2. Stepwise and one-pot syntheses of isoxazoles 4a–g.

M. F. A. Adamo, M. Nagabelli / Tetrahedron Letters 48 (2007) 4703–4706
NO2
4705
NHCOCH3
O
NHCOCH3
1. SnCl2/ HCl/THF, 25 oC, 2 h;
2. AcCl, TEA, CH2Cl2 ,
0 oC to 20 oC, 30 min
Oxone®, NaHCO3
Acetone, H2O
N
N
N
O
O
O
1a-g
Ar
4a-g
Ar
Ar
5a-g
1. SnCl2/ HCl/THF, 25 oC, 2 h;
2. AcCl, TEA, CH2Cl2 , 0 oC to 20 oC, 30 min
3. Oxone®, NaHCO3, Acetone, H2O
Scheme 3. Epoxidation of 3-methyl-4-N-acetyl-5-styryl isoxazoles.
use for the preparation of polyhydroxylated synthons
are in progress.
phase concentrated in vacuo, and the residue taken up
in chloroform (10 mL). The chloroform layer was
washed with brine, dried over Na2SO4 and finally evap-
orated to give pure 5a (0.490 g, 95% yield) as a colour-
less oil.
2. General procedure for the preparation of
compounds 4 (Table 1)
N-[3-Methyl-5-(3-phenyl-oxiranyl)-isoxazol-4-yl]-acet-
amide 5a: dH (400 MHz, CDCl3) 7.31–7.22 (5H, m,
Ar-H), 4.32–4.31 (1H, d, J = 2 Hz, O–CH), 3.92 (1H,
d, J = 2 Hz, O–CH), 2.14 (3H, s, COCH3), 2.07 (3H,
s, CH3); dc (100.6 MHz) 169.4, 158.8, 158.2, 135.1,
128.8, 128.7, 125.6, 116.6, 59.3, 54.1, 23.0, 10.0; HRMS
found: [M+] 258.1031, C14H14N2O3 requires 258.1004;
m/z: 258 (100%, M+).
To a solution of 3-methyl-4-nitro-5-styrylisoxazole 1a
(0.46 g, 2 mmol) in THF was added SnCl2Æ2H2O
(1.35 g, 6 mmol) followed by dropwise addition of conc.
HCl (4 mL). The reaction mixture was stirred at room
temperature for 2 h, then poured into a cold solution
of 10% NaOH (40 mL) and extracted with ethyl acetate
(2 · 20 mL). The combined organic layer was dried and
concentrated in vacuo, then treated with H2O (50 mL)
and extracted with CH2Cl2 (2 · 15 mL). The combined
organic layer was washed with brine, dried over
Na2SO4, filtered and cooled to 0–5 ꢂC. Next, acetyl chlo-
ride (0.23 mL) and triethylamine (0.45 mL) were added
dropwise, the reaction mixture was allowed to reach
room temperature and then stirred for 30 min. After this
time, the reaction was diluted with CH2Cl2 (30 mL),
washed with water, then brine, dried over Na2SO4, fil-
tered and finally concentrated to obtain title compound
4a as a colourless solid (0.415 g, 86% yield).
Acknowledgement
We would like to acknowledge the PTRLI cycle III for a
grant to M.N.
References and notes
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N-(3-Methyl-5-styryl-isoxazol-4-yl)-acetamide 4a: dH
(400 MHz, CDCl3) 7.40–7.38 (2H, m, Ar-H), 7.30–7.29
(3H, m, Ar-H), 7.24 (1H, br s, NH), 7.17–7.16 (1H, m,
CH), 6.70 (1H, d, J = 16, CH), 2.12 (6H, s, COCH3,
CH3): dc (100.6 MHz) 169.6, 161.2, 158.4, 135.5, 134.5,
129.0, 128.8, 127.4, 113.7, 111.0, 23.1, 9.8; HRMS
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3. General one-pot procedure for the preparation of
compounds 5 (Table 2)
To a solution of N-(3-methyl-5-styryl-isoxazol-4-yl)-
acetamide, 4a (0.516 g, 2 mmol) in acetone (50 mL)
was added water (25 mL) followed by NaHCO3 (1 g,
12 mmol, 6 equiv). The reaction mixture was cooled to
5 ꢂC and then added to a solution of Oxoneꢁ (1.89 g,
3 mmol, 1.5 equiv) in water (25 mL) maintaining the
temperature at 5–10 ꢂC. The reaction mixture was stir-
red for 2 h at 5–10 ꢂC, then brought to room tempera-
ture and stirred for a further 10 h. After this time, the
inorganic salts were removed by filtration, the liquid

4706
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