Synthesis of 4-oxo-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazole-3-carboxylic acid esters

Article abstract of DOI:10.1081/SCC-120030749

3-Imidazoline 3-oxides react regioselectively with 3-phenylpropanoic acid alkyl esters to give the corresponding 2-phenyl-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazole-3-carboxylic acid alkyl esters. This adducts convert to imidazole and the corresponding al

Full text of DOI:10.1081/SCC-120030749

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 9, pp. 1617–1623, 2004
Synthesis of 4-Oxo-3a,4,5,6-
tetrahydroimidazo[1,5-b]isoxazole-
3-carboxylic Acid Esters
*
Necdet Cos¸kun and Bilal Yılmaz
˘
¨ ¨
Department of Chemistry, Uludag University, Gorukle Bursa, Turkey
ABSTRACT
3-Imidazoline 3-oxides react regioselectively with 3-phenylpropanoic
acid alkyl esters to give the corresponding 2-phenyl-3a,4,5,6-tetrahydro-
imidazo[1,5-b]isoxazole-3-carboxylic acid alkyl esters. This adducts con-
vert to imidazole and the corresponding alkyl 3-oxo-3-phenylpropanoic
acid esters when treated with alkoxides or heated under vacuum. Attempts
to oxidise the carbon–carbon double bond using KMnO4–FeSO4 led
to the formation of heretofore unknown 4-oxo-3a,4,5,6-tetrahydro-
imidazo[1,5-b]isoxazoles.
Key Words: Imidazole; Heterocycles; Adducts; Nitrones.
*
˘
Correspondence: Necdet Cos¸kun, Department of Chemistry, Uludag University,
¨ ¨
16059-Gorukle Bursa, Turkey; E-mail: coskun@uludag.edu.tr.
1617
DOI: 10.1081/SCC-120030749
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Cos¸kun and Yılmaz
RESULTS AND DISCUSSIONS
The nitrones make possible the derivatisation of carbonyl compounds
through forming a five-membered heterocycles and their decomposition.
They readily undergo cycloaddition reactions with a wide variety of
carbon–carbon, carbon–nitrogen, carbon–sulphur, and nitrogen–phosphorus
multiple bond systems to provide various heterocyclic five-membered ring
systems.[1–4] The cycloadducts of cyclic nitrones[5] 1 with variety of dipolaro-
philes[6] give bicyclic compounds with potentially interesting biological
activity.a On the other hand, they are sours of new heterocyclic compounds
via interesting ring-opening reactions.[7]
We report herein the regioselective 1,3-dipolar cycloaddition of cyclic
nitrones 1 to give 3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazoles 2 (Sch. 1,
Table 1). Their oxidation to 4-oxo-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxa-
zoles with KMnO4–FeSO4 mixture and the thermal and base induced ring-
opening reactions will also be reported.
Cyclic nitrones 1 were refluxed in toluene in the presence of equimolar
amounts of alkyl phenylpropinoates for 24 hr to give regioselectively the
corresponding 2-phenyl-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazoles 2. The
1
structure was deduced from their IR and H NMR spectra. IR (KBr) spectra
of adducts 2 show a nC55O at 1700 cm21 and nC55C at 1660 cm21. Characteristic
singlets at 3.59 (3H) in the spectra of 2c and d correspond to the ester methoxy
group linked to C-3. This is in agreement with the assignments in the spectra
of DMAD adducts. Parts of the two AB systems corresponding to C-4 and C-6
are appearing at 3.69 (1H, d, J ¼ 9.9), 4.40 (1H, d, J ¼ 10.4), 4.75 (1H, d,
J ¼ 9.9), 5.10 (1H, d, J ¼ 10.4).
Scheme 1.
aA series of tetrahydroimidazo compounds were tested for their anticancer activity and
found to be quite active at 1025 molar concentrations.

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4-Oxo-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazoles
Table 1. 3a,4,5,6-Tetrahydroimidazo[1,5-b]isoxazoles.
1619
R
R1
R2
R3
Yield (%)
Mp (8C)
2a
2b
2c
2d
2e
Et
Et
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
4-MeC6H4
H
H
H
H
Ph
Ph
Ph
Ph
Ph
90
92
90
95
97
117–120
110–114
137–138
109–110
129 lit.[6e]
mp 129
Me
Me
Me
CO2Me
3a
3b
3e
4a
Et
Et
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
H
Ph
Ph
60
65
Oil
Oil
H
Me
Et
Ph
H
CO2Me
Ph
55
90a (95)b
Oil
131 lit.[7a] mp
134–135
103 lit.[7a] mp
100–101
4b
Et
4-MeOC6H4
H
Ph
92a (96)b
aYields of the base induced ring-opening.
bYields of the thermal ring-opening.
Adducts 2 were heated under vacuum for 15 min to give the correspon-
ding imidazoles[7a] and alkyl 3-oxo-3-phenylpropanoate which is a further
evidence for the formation of 2-phenyl regioisomer (Sch. 2).b
The treatment of adducts 2 with an excess of KMnO4–FeSO4 at ice cool-
ing for short time led to the formation of products having a second carbonyl
absorption in their IR spectra at 1750, beside the absorptions at 1710 cm21
corresponding to the ester carbonyl and nC55C at 1660 cm21. The AB system
centred at 4.52 ppm assigned to C-6 methylene remains unchanged as well
as remains the peak at 73.5 ppm in the 13C NMR spectrum assigned to C-6.
1
The H NMR spectrum of the oxidation product of adduct 2e shows only a
singlet at 6.18 corresponding to C-6 proton and the carbonyl absorption is
again at 1760 cm21
.
EXPERIMENTAL
Melting points were taken on an electrothermal digital melting point
apparatus. Infrared spectra were recorded on a Mattson 1000 FTIR. Proton
bThe spectra of alkyl 3-oxo-3-phenylpropanoates were compared with the IR spectra of
those obtained by Jons oxidation of the 3-hydroxy-3-phenylpropanoates. The latter
were prepared from the Reformatsky reaction of alkyl bromoacetates and benzaldehyde.

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Cos¸kun and Yılmaz
Scheme 2.
magnetic resonance spectra were recorded on a Bruker Dpx 400 MHz spec-
trometer. All spectra were taken in deuteriochloroform. Mass spectra were
routinely recorded at 70 eV by electron impact. Visualisation was effected
with UV light. Freshly prepared imidazoline 3-oxides were used after recrys-
tallization from either ethanol or acetone.
Tetrahydroimidazo[1,5-b]isoxazolines 2. General Procedure
To a solution of imidazoline 3-oxide 1 (5 mmol) in toluene (20 mL) alkyl
phenylpropinoate (5.2 mmol) was added. The mixture was refluxed for 24 hr.
The solvent was removed under vacuum. The product was recrystallised from
ethanol.
Ethyl-2,3a-diphenyl-5-(p-tolyl)-3a,4,5,6-tetrahydroimidazo[1,5-b]iso-
xazole-3-carboxylate 2a. Yield 90%; mp: 117–1208C; IR (KBr) nC55O
1700 cm21; nC55C 1660 cm21. Anal. Calcd for C27H26N2O3 (426.52) C,
76.03; H, 6.14; N, 6.57; Found C, 76.10; H, 6.15; N, 6.55.
Ethyl 2,3a-phenyl-5-(p-methoxyphenyl)-3a,4,5,6-tetrahydroimidazo
[1,5-b]isoxazole-3-carboxylate 2b. Yield 92%; mp: 110–1148C; IR (KBr)
nC55O 1700 cm21; nC55C 1660 cm21. Anal. Calcd for C27H26N2O4 (442.52) C,
73.29; H, 5.92; N, 6.33; Found C, 73.35; H, 5.90; N, 6.38.
Methyl-2,3a-diphenyl-5-(p-tolyl)-3a,4,5,6-tetrahydroimidazo[1,5-b]
isoxazole-3-carboxylate 2c. Yield 92%; mp: 137–1388C; IR (KBr) nC55O
1
1700 cm21; nC55C 1660 cm21. H NMR d 2.34 (3H, s), 3.59 (3H, s), 3.69
(1H, d, J ¼ 9.9), 4.40 (1H, d, J ¼ 10.4), 4.75 (1H, d, J ¼ 9.9), 5.10 (1H,
d, J ¼ 10.40), 6.79 (2H, d, J ¼ 8.3), 7.15 (2H, d, J ¼ 8.3), 7.27–7.52
(6H, m), 7.66 (2H, d, J ¼ 7.4), 7.72 (2H, d, J ¼ 7.6). Anal. Calcd for

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4-Oxo-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazoles
1621
C26H24N2O3 (412.49) C, 75.71; H, 5.86; N, 6.79; Found C, 75.68; H, 5.89;
N, 6.81.
Methyl-2,3a-phenyl-5-(p-methoxyphenyl)-3a,4,5,6-tetrahydroimidazo
[1,5-b]isoxazole-3-carboxylate 2d. Yield 95%; mp: 109–1108C; IR (KBr)
1
nC55O 1700 cm21; nC55C 1660 cm21. H NMR d 3.45 (3H, s), 3.50 (1H, d,
J ¼ 9.8), 3.69 (3H, s), 4.20 (1H, d, J ¼ 10.4), 4.58 (1H, d, J ¼ 9.8), 4.94
(1H, d, J ¼ 10.4), 6.71 (2H, d, J ¼ 8.9), 6.78 (2H, d, J ¼ 8.9), 7.13–7.42
(6H, m), 7.54 (2H, d, J ¼ 7.3), 7.58 (2H, d, J ¼ 7.7). Anal. Calcd for
C26H24N2O4 (428.49) C, 72.88; H, 5.65; N, 6.54; Found C, 72.80; H, 5.61;
N, 6.55.
Oxidation of Tetrahydroimidazo[1,5-b]isoxazoles with
Potasium Permanganate. General Procedure[8]
.
To the powdered mixture of KMnO4 (2 g, 12 mmol) and FeSO4 7H2O
(1 g, 4 mmol) in a reaction flask water (0.1 mL) and dichloromethane
(10 mL) was added. The mixture was cooled in an ice bath. Tetrahydroimi-
dazo[1,5-b]isoxazole (1 mmol) dissolved in 0.5 mL t-BuOH was added and
the mixture stirred for 15 min. The ice cooling was removed and after addition
of 15 mL of ether the mixture was stirred for more 15 min at room tempera-
ture. The reaction mixture was filtered through a celite bad and dried over
anhydrous Na2SO4. The solvent was evaporated on a rotary evaporator and
the residue was subjected to silica gel packed column. Ethyl acetate petroleum
ether was used as eluent.
2,3a-Diphenyl-5-p-tolyl-4-oxo-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxa-
zole-3-carboxylic acid ethyl ester 3a. Yield 60%; IR (film); nC55O 1750,
1
1710 cm21, nC55C 1660 cm21. H NMR d 0.96 (3H, t, J ¼ 7.1), 2.18 (3H, s),
3.93 (2H, q, J ¼ 7.1), 4.08 (1H, d, J ¼ 9.8), 4.97 (1H, d, J ¼ 9.8), 7.04 (2H,
d, J ¼ 8.5), 7.17–7.33 (6H, m), 7.41 (2H, d, J ¼ 8.5), 7.58 (2H, d, J ¼ 7.4),
7.62 (2H, d, J ¼ 7.4); 13C NMR d 14.2, 21.2, 52.7, 61.0, 73.5, 106.7, 119.4,
126.0, 126.7, 128.1, 128.7, 129.2, 130.1, 131.1, 132.1, 135.2, 135.9, 141.5,
160.3, 163.3, 165.6. MS C27H24N2O4 (440.50) m/z 440 (Mþ).
5-(4-Methoxy-phenyl)-4-oxo-2,3a-diphenyl-3a,4,5,6-tetrahydroimidazo
[1,5-b]isoxazole-3-carboxylic acid ethyl ester 3b. Yield 65%; IR (film); nC55O
1750, 1710cm21, nC55C 1660cm21; 1H NMR d 1.15 (3H, t, J ¼ 7.1), 3.82 (3H,
s), 3.93 (2H, q, J ¼ 7.1), 4.26 (1H, d, J ¼ 9.8), 5.14 (1H, d, J ¼ 9.8), 6.98 (2H,
d, J ¼ 8.5), 7.20–7.50 (6H, m), 7.61 (2H, d, J ¼ 8.5), 7.73–7.80 (4H, m) MS
C27H24N2O5 (456.50) m/z 456 (Mþ).
4-Oxo-3a-phenyl-5-p-tolyl-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazole-
2,3-dicarboxylic acid dimethyl ester 3e. Yield 55%; IR (neat); nC55O 1760,
1710 cm21, nC55C 1660 cm21. 1H NMR d 2.28 (3H, s), 3.72 (3H, s), 3.95 (3H,

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Cos¸kun and Yılmaz
s), 6.18 (1H, s), 7.12 (2H, d, J ¼ 8.2), 7.20–7.34 (10H, m), 7.76 (2H, d,
J ¼ 8.2) MS C28H24N2O6 (484.51) m/z 456 (Mþ 2 28).
Base Induced Ring-Opening Reactions of Isoxazoles 2
To a solution of sodium alkoxide in methanol (30 mL, 9.5 mmol
Na, 0.219 g) 3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazole-3-carboxylate
2
(3.17 mmol) was added. The mixture was refluxed for 2 hr. The solvent was
evaporated and water was added to the residue and extracted with chloroform.
The products were separated by column chromatography.
ACKNOWLEDGMENT
The financial support of Uludag University Research Fund is gratefully
acknowledged (Projects 2001-2 and 2000-35).
REFERENCES
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¨

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