Synthesis of isoxazole-5-carboxylates by cyclization of oxime 1,4-dianions with diethyl oxalate

Article abstract of DOI:10.1055/s-2006-942464

The cyclization of oxime dianions with diethyl oxalate afforded 4,5-dihydro-5-hydroxyisoxazole-5-carboxylates, which were transformed into isoxazole-5-carboxylates by acid-mediated dehydration. The reaction of the dilithiated oximes of cycloheptanone and

Full text of DOI:10.1055/s-2006-942464

PAPER
2515
Synthesis of Isoxazole-5-carboxylates by Cyclization of Oxime 1,4-Dianions
with Diethyl Oxalate
I
soxazole-5-carb
u
oxylates by
a
Cyclizationof Oxime 1,4-Dia
T
nions
w
ith
D
iet
h
hyl
O
xalate anh Dang,a,b Uwe Albrecht,b Peter Langer*a,c
a
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
b
c
Institut für Biochemie, Universität Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany
Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 7 December 2005; revised 23 March 2006
subsequently, for 15 minutes at 20 °C. In fact, the condi-
tions used for the generation of the dianion played a cru-
cial role. Diethyl oxalate was added at –78 °C and the
solution was warmed to ambient temperature over 16
Abstract: The cyclization of oxime dianions with diethyl oxalate
afforded 4,5-dihydro-5-hydroxyisoxazole-5-carboxylates, which
were transformed into isoxazole-5-carboxylates by acid-mediated
dehydration. The reaction of the dilithiated oximes of cyclohep-
tanone and cyclooctanone resulted in the formation of 1,2-oxazin- hours. A saturated solution of ammonium chloride was
6-ones rather than isoxazoles.
used for the aqueous workup. The formation of 3a can be
explained by attack of the carbon atom of the dianion A
onto 2 and subsequent regioselective attack of the oxygen
atom onto the carbonyl rather than the ester group. Ketol
3a was transformed into isoxazole 4a by treatment with p-
toluenesulfonic acid (toluene, reflux).11
Keywords: cyclizations, dianions, oxalic acid derivatives, one-pot
reactions, oximes
Functionalized isoxazoles are present in a variety of natu-
ral products and represent useful synthetic building
blocks.1a They have shown considerable antimicrobial,
antifungal, and herbicide activity.1b The isoxazole moiety
is present in sulfonamide antibiotics (sulfisoxazoles, ox-
acillin, cloxacillin, and dicloxacillin),2 antirheumatic and
antiarthritic agents (leflunomide),3 anti-inflammatory
agents (isoxicam),3 and antileprous agents and it is also
present in a monoaminoxidase inhibitor used in psycho-
therapy.2 The antipicornavirus and antimuscarinic activity
of 5-alkyl-3-methylisoxazoles and 5-(aminomethyl)-3-
phenylisoxazoles has been recognized.4 A general ap-
proach to isoxazoles relies on 1,3-dipolar cycloaddition of
nitrile oxides with alkynes or with alkenes containing a
leaving group.3,5 Isoxazoles have been prepared by cy-
clization reactions6 of oxime dianions with esters,7 N,N-
dialkylbenzamides,8 and Weinreb amides.9 Recently, we
have reported the synthesis of 1,2-oxazines by cyclization
of oxime dianions with epibromohydrin.10 Herein, we re-
port a convenient synthesis of isoxazole-5-carboxylates
by cyclization of oxime dianions with diethyl oxalate.
The cyclization of diethyl oxalate with the dianions of
methyl- and methoxy-substituted acetophenone oximes
1a–f afforded the ketols 3a–f which were transformed into
isoxazoles 4a–f (Scheme 1, Table 1). The naphthyl-sub-
stituted isoxazoles 4g,h were prepared from acetonaph-
thone oximes 1g,h. Starting with the chloro-, fluoro-, and
trifluoromethyl-substituted acetophenone oximes 1i–k,
the ketols 3i–k were prepared; the latter were transformed
into the corresponding isoxazoles 4i–k. The reactions of
diethyl oxalate with the cyano- and nitro-substituted ace-
tophenone oximes 1l and 1m were unsuccessful (forma-
tion of a complex mixture). This can be explained by the
assumption that the generation of the required dianions
failed, due to side-reactions of the cyano and the nitro
group with n-butyllithium. The use of lithium diisopropyl-
amide (rather than n-butyllithium) was equally unsuccess-
ful.
O
OH
Me
O
N
O
i
OEt
OEt
N
+
EtO
OH
The reaction of the dianion of acetophenone oxime (1a),
generated using n-butyllithium (2.5 equiv), with diethyl
oxalate (2) afforded 4,5-dihydro-5-hydroxyisoxazole-5-
carboxylate 3a (Scheme 1, Table 1). During the optimiza-
tion, the employment of diethyl oxalate proved to be im-
portant; the use of oxalyl chloride or ethyl 2-chloro-2-
oxoacetate resulted in polymerization. In addition, the
temperature, reaction time, and workup conditions proved
to be important parameters. Best results were obtained
when the dianion was stirred for 45 minutes at –78 °C and,
Ar
O
Ar
1a–k
2
3a–k
ii
O
OLi
OLi
N
O
O
2
N
N
OEt
OEt
Li
Ar
Ar
Ar
O
B
A
4a–k
Scheme 1 Synthesis of isoxazoles 4a–k. Reagents and conditions:
(i) 1. n-BuLi (2.5 equiv), –78 °C, 45 min; 2. r.t., 15 min; 3. 2, –78 °C
to r.t., 16 h; (ii) TsOH·H2O (5.0 equiv), toluene, reflux, 6 h.
SYNTHESIS 2006, No. 15, pp 2515–2522
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-942464; Art ID: T16805SS
x
x.
x
x
.
2
0
0
6
© Georg Thieme Verlag Stuttgart · New York

2516
T. T. Dang et al.
PAPER
Table 1 Yields of 3a–k and 4a–k
ketol 3r and of 6,12-bicyclic 1,2-oxazin-6-one 5r. Ketol
3r was transformed into the 5,12-bicyclic isoxazole 4r.
The reaction of diethyl oxalate with the dianion of cyclo-
pentanone oxime failed (formation of a complex mixture).
3,4
Ar
Yielda (%)
3
4
a
b
c
d
e
f
Ph
40
42
37
54
43
35
45
51
39
52
41
0
94
82
79
96
68
75
82
76
74
79
85
–
O
OH
N
O
O
O
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-(MeO)C6H4
3-(MeO)C6H4
1-naphthyl
2-naphthyl
4-ClC6H4
N
N
OEt
+
i
OH
OH
()n
()n
()n
1o–r
3o,r
5p–r
O
O
N
ii
OEt
g
h
i
()n
4o,r
Scheme 3 Synthesis of 3o,r, 4o,r, and 5p–r. Reagents and condi-
tions: (i) 1. n-BuLi (2.5 equiv), –78 °C, 1 h; 2. r.t., 10 min; 3. 2, –78
°C to r.t., 16 h; (ii) TsOH·H2O (5.0 equiv), toluene, reflux, 6 h.
j
4-FC6H4
k
l
4-F3CC6H4
4-O2NC6H4
4-(NC)C6H4
Table 2 Products and Yields
3,4,5
n
Yielda (%)
m
0
–
3
4
5
a Yield of isolated product.
o
p
q
r
1
2
3
7
55
0
78
–
0
The cyclization of tetralone oxime (1n) with diethyl ox-
alate afforded the ketol 3n which was transformed into 4n
(Scheme 2).
47
39
21
0
–
53
62
O
OH
O
N
a Yield of isolated product.
N
OEt
OH
i
In conclusion, we have reported a convenient and regiose-
lective synthesis of isoxazole-5-carboxylates by cycliza-
tion of oxime dianions with diethyl oxalate and
subsequent dehydration. The reaction of the dilithiated
oximes of cycloheptanone and cyclooctanone resulted in
the formation of 1,2-oxazin-6-ones rather than isoxazoles.
1n
3n (57%)
ii
O
N
O
OEt
All solvents were dried by standard methods and all reactions were
performed under an inert atmosphere. For 1H and 13C NMR spectra
the deuterated solvents indicated were used. MS data was obtained
by electron ionization (EI, 70 eV) or chemical ionization (CI, H2O).
For preparative scale chromatography, silica gel (60–200 mesh)
was used. Melting points are uncorrected.
4n (91%)
Scheme 2 Synthesis of 3n and 4n. Reagents and conditions: (i) 1.
n-BuLi (2.5 equiv), –78 °C, 1 h; 2. r.t., 10 min; (3) 2, –78 °C to r.t.,
16 h; (ii) TsOH·H2O (5.0 equiv), toluene, reflux, 6 h.
Ethyl 4,5-Dihydro-5-hydroxyisoxazole-5-carboxylates 3; Gen-
eral Procedure
The cyclization of diethyl oxalate with the dianion of cy-
clohexanone oxime gave the ketol 3o which was trans- To a soln of oxime 1 in THF at –78 °C was added n-BuLi. The mix-
ture was stirred at this temperature for 45 min and then at r.t. for 15
min. The mixture was cooled to –78 °C and diethyl oxalate was add-
formed into the isoxazole 4o (Scheme 3, Table 2).
Surprisingly, the cyclization of diethyl oxalate with cyclo-
ed. The mixture was warmed to r.t. over 16 h and sat. aq NH4Cl (30
heptanone oxime afforded the 6,7-bicyclic 1,2-oxazin-6-
mL) was added. The organic and the aqueous layer were separated
one 5p rather than the expected isoxazole. Likewise, the
and the latter was extracted with EtOAc (3 × 30 mL). The combined
6,8-bicyclic 1,2-oxazin-6-one 5q was obtained in the cy-
clization of diethyl oxalate with cyclooctanone oxime.
The cyclization of diethyl oxalate with cyclododecanone
oxime resulted in the formation of a separable mixture of
organic layers were dried (Na2SO4) and filtered and the solvent was
removed from the filtrate in vacuo. The residue was purified by
chromatography (silica gel, n-hexane–EtOAc, 10:1 to 3:1).
Synthesis 2006, No. 15, 2515–2522 © Thieme Stuttgart · New York

PAPER
Isoxazole-5-carboxylates by Cyclization of Oxime 1,4-Dianions with Diethyl Oxalate
2517
Ethyl 4,5-Dihydro-5-hydroxy-3-phenylisoxazole-5-carboxylate
(3a)
Starting from oxime 1a (0.270 g, 2.0 mmol) in THF (20 mL) and us-
ing 2.5 M n-BuLi in hexane (2.0 mL, 5.0 mmol) and diethyl oxalate
(0.3 mL, 2.2 mmol) gave 3a as a slightly pink-colored solid; yield:
0.188 g (40%); mp 132 °C.
Ethyl 4,5-Dihydro-5-hydroxy-3-(2-methylphenyl)isoxazole-5-
carboxylate (3d)
Starting from oxime 1d (0.298 g, 2.0 mmol) in THF (20 mL) and
using 2.5 M n-BuLi in hexane (2.0 mL, 5.0 mmol) and diethyl ox-
alate (0.3 mL, 2.2 mmol) gave 3d as a yellow solid; yield: 0.269 g
(54%); mp 53 °C.
IR (KBr): 3229 (m), 2987 (w), 1743 (s), 1448 (m), 1363 (m), 1293
(m), 1215 (m) 1138 (m), 1077 (w), 912 (w), 760 (w), 690 cm–1 (w).
IR (KBr): 3442 (m), 2985 (w), 1734 (s), 1372 (w), 1304 (w), 1214
(s), 1134 (m), 893 (w), 757 cm–1 (m).
3
3
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.2 Hz, 3 H, CH3),
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.2 Hz, 3 H, CH3),
3.45 (d, 2J = 17.5 Hz, 1 H, CH2), 3.95 (d, 2J = 17.5 Hz, 1 H, CH2),
4.35 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 4.60 (br s, OH), 7.45 (m, 3 H,
Ar), 7.71 (m, 2 H, Ar).
2.61 (s, 3 H, CH3), 3.45 (d, J = 17.5 Hz, 1 H, CH2), 4.05 (d,
2
2J = 17.5 Hz, 1 H, CH2), 4.35 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 4.52
(br s, OH), 7.20–7.41 (m, 4 H, Ar).
13C NMR (75 MHz, CDCl3): d = 14.0 (CH2CH3), 44.0 (CH2), 63.5
(OCH2CH3), 103 (C), 126.9, 128.9, 130.7 (CH, Ar), 126.8 (C),
128.6 (C), 156.6 (CN), 168.3 (CO).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 23.3 (CH3), 46.2
(CH2), 63.5 (OCH2CH3), 102.3 (C), 126.4, 129.1, 130.3, 132.1 (CH,
Ar), 127.5, 138.3 (2C, Ar), 157.7 (CN), 168.3 (CO).
MS (EI, 70 eV): m/z (%) = 235 (M+, 15), 117 (16).
MS (EI, 70 eV): m/z (%) = 249 (M+, 29), 176 (100), 130 (71), 117
(14), 91 (81), 66 (18).
Anal. Calcd for C12H13NO4: C, 61.27; H, 5.57; N, 5.95. Found: C,
61.38; H, 5.67; N, 5.74.
Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found: C,
62.58; H, 6.08; N, 5.34.
Ethyl 4,5-Dihydro-5-hydroxy-3-(4-methylphenyl)isoxazole-5-
carboxylate (3b)
Starting from oxime 1b (0.298 g, 2.0 mmol) in THF (20 mL) and
using 2.5 M n-BuLi in hexane (2.0 mL, 5.0 mmol) and diethyl ox-
alate (0.3 mL, 2.2 mmol) gave 3b as a yellow solid; yield: 0.209 g
(42%); mp 135 °C.
Ethyl 4,5-Dihydro-5-hydroxy-3-(4-methoxyphenyl)isoxazole-5-
carboxylate (3e)
Starting from oxime 1e (0.332 g, 2.0 mmol) in THF (20 mL) and us-
ing 2.5 M n-BuLi in hexane (2.0 mL, 5.0 mmol) and diethyl oxalate
(0.3 mL, 2.2 mmol) gave 3e as a colorless solid; yield: 0.228 g
(43%); mp 122 °C.
IR (KBr): 3191 (m), 2986 (w), 1742 (s), 1361 (m), 1293 (m), 1209
(m), 1135 (m), 911 (m), 864 cm–1 (m).
IR (KBr): 3206 (m), 2981 (w), 1746 (s), 1607 (m), 1362 (m), 1297
(m), 1209 (m), 1134 (m), 1075 (w), 906 (w), 862 (m), 761 cm–1 (w).
3
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.2 Hz, 3 H, CH3),
2
3
2.40 (s, 3 H, CH3), 3.41 (d, J = 17.5 Hz, 1 H, CH2), 3.95 (d,
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.2 Hz, 3 H, CH3),
2J = 17.5 Hz, 1 H, CH2), 4.35 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 4.70
(br s, OH), 7.20 (d, 3J = 8.4 Hz, 2 H, Ar), 7.60 (d, 3J = 8.4 Hz, 2 H,
Ar).
3.41 (d, J = 17.5 Hz, 1 H, CH2), 3.85 (s, 3 H, OCH3), 3.95 (d,
2
2J = 17.5 Hz, 1 H, CH2), 4.35 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 4.60
(br s, OH), 6.96 (d, 3J = 9 Hz, 2 H, Ar), 7.60 (d, 3J = 9 Hz, 2 H, Ar).
13C NMR (75 MHz, CDCl3): d = 14.0 (CH3), 21.5 (CH3), 44.4
(CH2), 63.5 (OCH2CH3), 103.0 (C), 127.4, 129.9 (CH, Ar), 125.8,
141.0 (C, Ar), 156.5 (C, CN), 168.3 (CO).
13C NMR (75 MHz, CDCl3): d = 14.0 (CH2CH3), 44.1 (CH2), 55.4
(OCH3), 63.5 (OCH2CH3), 103.1 (C), 114.4, 128.6 (CH, Ar), 121.2,
161.7 (C, Ar), 156.2 (CN), 168.3 (CO).
MS (EI, 70 eV): m/z (%) = 249 (M+, 17), 176 (100), 158 (8), 134
MS (EI, 70 eV): m/z (%) = 265 (M+, 26), 192 (11), 149 (3).
(45), 117 (15), 91 (72), 66 (30).
Anal. Calcd for C13H15NO5: C, 58.86; H, 5.70; N, 5.28. Found: C,
58.90; H, 5.75; N, 5.11.
Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found: C,
62.33; H, 6.09; N, 5.32.
Ethyl 4,5-Dihydro-5-hydroxy-3-(3-methoxyphenyl)isoxazole-5-
carboxylate (3f)
Starting from oxime 1f (0.332 g, 2.0 mmol) in THF (20 mL) and
using 2.5 M n-BuLi in hexane (2.0 mL, 5.0 mmol) and diethyl ox-
alate (0.3 mL, 2.2 mmol) gave 3f as a colorless solid; yield: 0.186 g
(35%); mp 110 °C.
Ethyl 4,5-Dihydro-5-hydroxy-3-(3-methylphenyl)isoxazole-5-
carboxylate (3c)
Starting from soln of oxime 1c (0.298 g, 2.0 mmol) in THF (20 mL)
and using 2.5 M n-BuLi in hexane (2.0 mL, 5.0 mmol) and diethyl
oxalate (0.3 mL, 2.2 mmol) gave 3c as a colorless solid; yield: 0.184
g (37%); mp 91 °C.
IR (KBr): 3430 (m), 2977 (w), 1740 (s), 1609 (m), 1364 (m), 1296
(m), 1217 (m), 1135 (m), 1078 (w), 913 (w), 791 (w), 756 cm–1 (w).
IR (KBr): 3219 (m), 2983 (w), 1742 (s), 1368 (m), 1286 (m), 1210
(m), 1135 (m), 918 (m), 792 (m), 759 (m), 693 cm–1 (w).
3
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.2 Hz, 3 H, CH3),
3
2
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.2 Hz, 3 H, CH3),
3.41 (d, J = 17.5 Hz, 1 H, CH2), 3.85 (s, 3 H, OCH3), 3.95 (d,
2
2.41 (s, 3 H, CH3), 3.40 (d, J = 17.5 Hz, 1 H, CH2), 3.95 (d,
2J = 17.5 Hz, 1 H, CH2), 4.40 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 4.61
(br s, OH), 6.96 (dd, 3J = 8.3 Hz, 4J = 0.9 Hz, 1 H, Ar), 7.21–7.42
(m, 3 H, Ar).
2J = 17.5 Hz, 1 H, CH2), 4.35 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 4.50
(br s, OH), 7.30–7.45 (m, 3 H, Ar), 7.5 (m, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 14.0 (CH3), 21.3 (CH3), 44.0
(CH2), 63.9 (OCH2CH3), 103.1 (C), 124.4, 127.9, 129.1, 131.9 (CH,
Ar), 128.5, 138.6 (C, Ar), 156.7 (CN), 168.3 (CO).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH2CH3), 43.9 (CH2), 55.4
(OCH3), 63.5 (OCH2CH3), 103.2 (C), 111.4, 117.1, 119.6, 129.8
(CH, Ar), 129.8, 159.7 (C, Ar), 156.2 (CN), 168.3 (CO).
MS (EI, 70 eV): m/z (%) = 249 (M+, 11), 176 (100), 134 (56), 117
MS (EI, 70 eV): m/z (%) = 265 (M+, 19), 192 (100), 149 (27), 106.5
(18), 108 (22), 91 (98).
(31), 92 (20), 77 (32).
Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found: C,
62.71; H, 6.14; N, 5.45.
Anal. Calcd for C13H15NO5: C, 58.86; H, 5.70; N, 5.28. Found: C,
58.66; H, 5.80; N, 5.06.
Synthesis 2006, No. 15, 2515–2522 © Thieme Stuttgart · New York

2518
T. T. Dang et al.
PAPER
Ethyl 3-(4-Fluorophenyl)-5-hydroxy-4,5-dihydroisoxazole-5-
Ethyl 4,5-Dihydro-5-hydroxy-3-(1-naphthyl)isoxazole-5-car-
boxylate (3g)
carboxylate (3j)
Starting from oxime 1g (0.372 g, 2.0 mmol) in THF (20 mL) and us-
ing 2.5 M n-BuLi in hexane (2.0 mL, 5.0 mmol) and diethyl oxalate
(0.3 mL, 2.2 mmol) gave 3g as a brownish oil; yield: 0.257 g (45%).
Starting with a soln of oxime 1j (0.230 g, 1.5 mmol) in THF (20
mL) using 2.5 M n-BuLi in hexane (1.5 mL, 3.75 mmol) and diethyl
oxalate (0.25 mL, 1.8 mmol) gave 3j as a colorless solid; yield:
0.195 g (52%); mp 132 °C.
IR (KBr): 3452 (m), 2986 (w), 1739 (s), 1510 (m), 1370 (m), 1298
(m), 1215 (m), 1137 (m), 1076 (w), 898 (w), 865 (w), 778 cm–1 (w).
IR (KBr): 3193 (m), 2979 (w), 1747 (s), 1361 (m), 1292 (m), 1208
(m), 1135 (m), 913 (m), 867 cm–1 (m).
3
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.1 Hz, 3 H, CH3),
3.60 (d, 2J = 17.5 Hz, 1 H, CH2), 4.23 (d, 2J = 17.5 Hz, 1 H, CH2),
4.41 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 4.70 (br s, OH), 7.52 (m, 4 H,
Ar), 7.91 (m, 2 H, Ar), 8.90 (dd, 3J = 8.5 Hz, 4J = 0.8 Hz, 1 H, Ar).
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.2 Hz, 3 H, CH3),
3
3.42 (d, 2J = 17.5 Hz, 1 H, CH2), 3.95 (d, 2J = 17.5 Hz, 1 H, CH2),
4.35 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 4.82 (br s, OH), 7.14 (d, 2 H,
Ar), 7.71 (d, 2 H, Ar).
13C NMR (75 MHz, CDCl3): d = 14.05 (CH2CH3), 46.7 (CH2), 63.6
(OCH2CH3), 103.2 (C), 124.8, 126.5, 126.9, 127.7, 128.1, 128.7,
131.4 (CH, Ar), 125.6, 130.6 (C, Ar), 133.9 (C, Ar), 157.3 (CN),
168.3 (CO).
13C NMR (75 MHz, CDCl3): d = 14.4 (CH2CH3), 44.3 (CH2), 63.9
(OCH2CH3), 103.7 (C), 116.3, 116.6 (3J = 4.2 Hz, CH, Ar), 129.3,
1
129.3 (CH, Ar), 156.0 (C), 164.5 (d, J = 250.8 Hz, CF), 166.1
(CN), 168.5 (CO).
MS (EI, 70 eV): m/z (%) = 253 (M+, 1), 180 (100), 138 (82), 121
MS (EI, 70 eV): m/z (%) = 285 (M+, 37), 212 (25), 185 (42), 166
(100), 152 (37), 127 (78), 77 (11).
(59), 109 (20), 75 (23).
HRMS (EI, 70 eV): m/z (M+) calcd for C12H12FNO4: 253.0745;
Anal. Calcd for C16H15NO4: C, 67.36; H, 5.30; N, 4.91. Found: C,
67.84; H, 5.51; N, 4.75.
found: 253.0749.
Ethyl 4,5-Dihydro-5-hydroxy-3-(2-naphthyl)isoxazole-5-car-
boxylate (3h)
Starting from oxime 1h (0.372 g, 2.0 mmol) in THF (20 mL) and
using 2.5 M n-BuLi in hexane (2.0 mL, 5.0 mmol) and diethyl ox-
alate (0.3 mL, 2.2 mmol) gave 3h as a colorless solid; yield: 0.291
g (51%); mp 121 °C.
Ethyl
5-Hydroxy-4,5-dihydro-3-[3-(trifluoromethyl)phe-
nyl]isoxazole-5-carboxylate (3k)
Starting with a soln of oxime 1k (0.406 g, 2.0 mmol) in THF (20
mL) using 2.5 M n-BuLi in hexane (2.0 mL, 5.0 mmol) and diethyl
oxalate (0.3 mL, 2.2 mmol) gave 3k as a colorless solid; yield: 0.252
g (41%); mp 132 °C.
IR (KBr): 3455 (m), 1726 (s), 1308 (m), 1225 (s), 1124 (m), 889
(w), 823 (w), 751 cm–1 (w).
IR (KBr): 3198 (m), 2981 (w), 1749 (s), 1361 (m), 1290 (m), 1203
(m), 1131 (m), 923 (m), 861 cm–1 (m).
3
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.2 Hz, 3 H, CH3),
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.2 Hz, 3 H, CH3),
3
3.55 (d, 2J = 17.5 Hz, 1 H, CH2), 4.10 (d, 2J = 17.5 Hz, 1 H, CH2),
4.41 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 4.73 (br s, OH), 7.51 (m, 2 H,
Ar), 7.85 (m, 3 H, Ar), 7.95 (m, 2 H, Ar).
3.42 (d, 2J = 17.5 Hz, 1 H, CH2), 3.93 (d, 2J = 17.5 Hz, 1 H, CH2),
4.25 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 4.82 (br s, OH), 7.52 (m, 1 H,
Ar), 7.63 (d, 1 H, Ar), 7.93 (m, 2 H, Ar).
13C NMR (75 MHz, CDCl3): d = 14.0 (CH2CH3), 43.8 (CH2), 63.6
(OCH2CH3), 103.3 (C), 123.5, 126.8, 127.4, 127.5, 127.9, 128.5,
128.7 (CH, Ar), 126.2, 132.9 (C, Ar), 134.2 (C, Ar), 156.7 (CN),
168.3 (CO).
MS (EI, 70 eV): m/z (%) = 285 (M+, 1), 212 (34), 152 (148), 127
(44).
13C NMR (75 MHz, CDCl3): d = 14.3 (CH2CH3), 43.9 (CH2), 64.1
(OCH2CH3), 104.1 (C), 123.6 (q, 3J = 3.5 Hz, CH, Ar), 127.1 (q,
3J = 3.5 Hz, CH, Ar), 129.4, 130.2 (CH, Ar), 124.3 (q, J = 272.3
1
Hz, CF), 125.8 (C), 131.7 (q, 2J = 32.8 Hz, C), 155.9 (CN), 168.3
(CO).
MS (EI, 70 eV): m/z (%) = 303 (M+, 5), 230 (100), 171 (27), 145
(61), 121 (5), 75 (6).
HRMS (EI, 70 eV): m/z (M+) calcd for C13H12F3NO4: 303.0713;
Anal. Calcd for C16H15NO4: C, 67.36; H, 5.30; N, 4.91. Found: C,
67.06; H, 5.31; N, 4.75.
found: 303.0706.
Ethyl 3-(4-Chlorophenyl)-4,5-dihydro-5-hydroxyisoxazole-5-
carboxylate (3i)
Ethyl 3,3a,4,5-Tetrahydro-3-hydroxynaphtho[1,2-c]isoxazole-
3-carboxylate (3n)
Starting with a soln of oxime 1n (0.322 g, 2.0 mmol) in THF (20
mL) using 2.5 M n-BuLi in hexane (2.0 mL, 5.0 mmol) and diethyl
oxalate (0.3 mL, 2.2 mmol) gave 3n as a slightly brown-colored sol-
id; yield: 0.298 g (57%); mp 181 °C.
Starting from oxime 1i (0.340 g, 2.0 mmol) in THF (20 mL) and us-
ing 2.5 M n-BuLi in hexane (2.0 mL, 5.0 mmol) and diethyl oxalate
(0.3 mL, 2.2 mmol) gave 3i as a slight brownish solid; yield: 0.212
g (39%); mp 132 °C.
IR (KBr): 3192 (m), 2985 (w), 1749 (s), 1366 (m), 1297 (m), 1203
(m), 1137 (m), 917 (m), 869 cm–1 (m).
IR (KBr): 3405 (m), 2956 (w), 1740 (s), 1462 (w), 1366(w), 1295
(m), 1217 (m), 1173 (m), 1077 (w), 1051 (w), 846 (w), 769 cm–1
(w).
3
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.2 Hz, 3 H, CH3),
3.42 (d, 2J = 17.5 Hz, 1 H, CH2), 3.91 (d, 2J = 17.5 Hz, 1 H, CH2),
4.25 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 7.48 (d, 2 H, Ar), 7.71 (d, 2
H, Ar).
3
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.1 Hz, 3 H, CH3),
2.05–2.15 (m, 2 H, CH2), 2.92–3.13 (m, 2 H, CH2), 3.91–4.04 (m, 1
13C NMR (75 MHz, CDCl3): d = 14.0 (CH2CH3), 44.6 (CH2), 62.0
(OCH2CH3), 104.6 (C), 128.6, 128.6, 128.9, 128.9 (CH, Ar), 127.8,
135.2 (C), 155.8 (CN), 167.9 (CO).
MS (EI, 70 eV): m/z (%) = 270 (M+, 1), 196 (100), 154 (70), 137
(39), 111 (45), 75 (23).
HRMS (EI, 70 eV): m/z (M+) calcd for C12H12ClNO4: 269.0449;
found: 269.0451.
3
H, CH), 4.41 (q, J = 7.2 Hz, 2 H, OCH2CH3), 4.55 (br s, OH),
7.10–7.42 (m, 3 H, Ar), 8.02 (m, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH2CH3), 21.7, 29.9 (CH2),
52.2 (CH), 63.9 (OCH2CH3), 102.5 (C), 126.1, 127.3, 129.3, 131.3
(CH, Ar), 124.8, 140.2 (2 C, Ar), 157.3 (CN), 168.3 (CO).
MS (EI, 70 eV): m/z (%) = 261 (M+, 24), 188 (62), 160 (61), 140 (4),
132 (34), 115 (36).
Synthesis 2006, No. 15, 2515–2522 © Thieme Stuttgart · New York

PAPER
Isoxazole-5-carboxylates by Cyclization of Oxime 1,4-Dianions with Diethyl Oxalate
2519
Ethyl 3,3a,4,5,6,7-Hexahydro-3-hydroxy-2,1-benzisoxazole-3-
carboxylate (3o)
Starting with a soln of oxime 1o (0.226 g, 2.0 mmol) in THF (20
mL) using 2.5 M n-BuLi in hexane (2.0 mL, 5.0 mmol) and diethyl
oxalate (0.3 mL, 2.2 mmol) gave 3o as a colorless solid; yield: 0.234
g (55%); mp 61 °C.
Ethyl 3-Phenylisoxazole-5-carboxylate (4a); Typical Procedure
To a soln of 3a (0.100 g, 0.43 mmol) in toluene (20 mL) was added
TsOH·H2O (0.405 g, 2.1 mmol) and the soln was refluxed for 6 h.
The mixture was cooled to r.t. and sat. NaHCO3 (20 mL) was added
and the mixture was stirred for 15 min at r.t. The organic and aque-
ous layers were separated and the latter was extracted with EtOAc
(2 × 30 mL). The combined organic layers were dried (Na2SO4), fil-
tered, and the solvent removed from the filtrate in vacuo. The resi-
due was purified by chromatography (silica gel, n-hexane–EtOAc,
3:1) to give 4a as a brownish oil; yield: 0.087 g (94%).
IR (KBr): 3464 (m), 2942 (m), 1721 (s), 1452 (w), 1302 (m), 1236
(w), 1185 (s), 1098 (w), 1050 (w), 837 (m), 562 cm–1 (w).
3
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.1 Hz, 3 H, CH3),
1.41–1.56 (m, 2 H, CH2), 1.65–2.04 (m, 4 H, CH2), 2.12–2.25 (m, 1
IR (KBr): 3428 (w), 2982 (w), 1723 (s), 1447 (s), 1292 (s), 1245 (s),
1024 (m), 768 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 1.35 (t, 3J = 7.2 Hz, 3 H,
OCH2CH3), 4.35 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 7.25 (s, 1 H, CH),
7.42 (m, 3 H, Ar), 7.81 (m, 2 H, Ar).
13C NMR (75 MHz, CDCl3): d = 14.5 (CH2CH3), 62.7 (OCH2CH3),
107.7 (CH), 127.2, 129.5, 129.5, 130.9 (CH, Ar), 128.2 (C, Ar),
157.2 (C), 161.3 (CN), 163.3 (CO).
MS (EI, 70 eV): m/z (%) = 217 (M+, 92), 172 (21), 155 (10), 144
(100), 116 (63), 103 (13), 89 (14), 77 (68).
HRMS (EI, 70 eV): m/z (M+) calcd for C12H11NO3: 217.0733;
3
H, CH2), 2.83–2.90 (m, 1 H, CH2), 3.42–3.51 (dd, J = 8.2 Hz,
3J = 4.0 Hz, 1 H, CH), 4.35 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 4.45
(br s, OH).
13C NMR (75 MHz, CDCl3): d = 13.7 (CH2CH3), 23.3, 23.7, 24.3,
25.1 (CH2), 52.2 (CH), 62.9 (OCH2CH3), 101.6 (C), 159.6 (CN),
168.8 (CO).
MS (EI, 70 eV): m/z (%) = 213 (M+, 3), 140 (65), 122 (57), 94 (68),
55 (100).
Anal. Calcd for C10H15NO4: C, 56.33; H, 7.09; N, 6.57. Found: C,
55.86; H, 7.10; N, 6.26.
Ethyl 3,3a,4,5,6,7,8,9,10,11,12,13-Dodecahydro-3-hydroxy-
cyclododec[c]isoxazole-3-carboxylate (3r) and
5,6,7,8,9,10,11,12,13,14-Decahydro-4-hydroxy-3H-cyclo-
found: 217.0734.
Ethyl 3-(4-Methylphenyl)isoxazole-5-carboxylate (4b)
Starting from 3b (0.103 g, 0.407 mmol) in toluene (20 mL) and us-
ing TsOH·H2O (0.405 g, 2.1 mmol) gave 4b as a slightly brown sol-
id; yield: 0.077 g (82%).
dodec[c][1,2]oxazin-3-one (5r)
Starting with a soln of oxime 1r (0.394 g, 2.0 mmol) in THF (20
mL) and using 2.5 M n-BuLi in hexane (2.0 mL, 5.0 mmol) and di-
ethyl oxalate (0.3 mL, 2.2 mmol) gave 3r as a colorless solid; yield:
0.315 g (53%); mp 79 °C; 5r was also obtained as a yellow solid;
yield: 0.105 g (21%); mp 174 °C.
IR (KBr): 3434 (w), 2985 (w), 1728 (s), 1447 (w), 1294 (s), 1248(s),
1016 (w), 922 (w), 820 (s), 766 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 1.35 (t, 3J = 7.2 Hz, 3 H,
OCH2CH3), 2.41 (s, 3 H, CH3), 4.35 (q, 3J = 7.2 Hz, 2 H,
OCH2CH3), 7.25 (s, 1 H, CH), 7.35 (d, 2 H, Ar), 7.71 (d, 2 H, Ar).
13C NMR (75 MHz, CDCl3): d = 14.5 (CH2CH3), 21.5 (CH3), 62.7
(OCH2CH3), 107.7 (CH), 127.4, 129.9 (CH, Ar), 12.8, 141.0 (C,
Ar), 157.2 (C), 161.3 (CN), 163.3 (CO).
3r:
IR (KBr): 3444 (s), 2932 (s), 1729 (s), 1250 (w), 1205 (m), 1023
(w), 849 cm–1 (m).
3
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.1 Hz, 3 H, CH3),
1.42–1.91 (m, 18 H, CH2), 2.18–2.29 (m, 1 H, CH2), 2.51–2.62 (m,
1 H, CH2), 3.67–3.7 (dd, 3J = 8.3 Hz, 3J = 4.0 Hz, 1 H, CH), 4.27–
4.41 (m, 2 H, OCH2CH3), 4.48 (br s, OH).
MS (EI, 70 eV): m/z (%) = 231 (M+, 65), 186 (5), 158 (100), 130
(63), 116 (6.6), 103 (8), 91 (35), 77 (9), 65 (21).
13C NMR (75 MHz, CDCl3): d = 14.0 (CH2CH3), 20.9, 23.1, 23.1,
23.6, 23.6, 24.0, 24.1, 24.4, 24.9, 25.9 (CH2), 52.9 (CH), 63.3
(OCH2CH3), 102.5 (C), 162.9 (CN), 169.4 (CO).
HRMS (EI, 70 eV): m/z (M+) calcd for C13H13NO3: 231.0889;
found: 231.0884.
MS (EI, 70 eV): m/z (%) = 297 (M+, 3), 224 (100), 178 (37), 140 (3),
136 (39), 122 (44), 86 (16).
Ethyl 3-(3-Methylphenyl)isoxazole-5-carboxylate (4c)
Starting with 3c (0.102 g, 0.41 mmol) in toluene (20 mL) and using
TsOH·H2O (0.405 g, 2.1 mmol) gave 4c as a brownish oil; yield:
0.074 g (79%).
Anal. Calcd for C16H27NO4: C, 64.62; H, 9.15; N, 4.71. Found: C,
64.33; H, 9.22; N, 4.62.
IR (KBr): 3438 (w), 2988 (w), 1730 (s), 1441 (m), 1288 (s), 1258
(s), 1034 (m), 768 (m), 703 cm–1 (m).
5r:
1H NMR (300 MHz, CDCl3): d = 1.35 (t, 3J = 7.2 Hz, 3 H,
OCH2CH3), 2.41 (s, 3 H, CH3), 4.35 (q, 3J = 7.2 Hz, 2 H,
OCH2CH3), 7.25 (s, 1 H, CH), 7.42 (m, 2 H, Ar), 7.63 (d, 1 H, Ar),
7.68 (s, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 14.7 (CH2CH3), 21.6 (CH3), 62.9
(OCH2CH3), 107.7 (CH), 124.2, 127.7, 129.5, 132.1 (CH, Ar),
140.4 (C, Ar), 157.8 (C), 161.3 (CN), 163.3 (CO).
MS (EI, 70 eV): m/z (%) = 231 (M+, 92), 186 (19), 158 (100), 130
(75), 116 (16), 103 (19), 91 (91), 77 (23), 65 (67).
HRMS (EI, 70 eV): m/z (M+) calcd for C13H13NO3: 231.0889;
found: 231.0887.
IR (KBr): 3328 (m), 2932 (s) 1688 (s), 1647 (m), 1383 (s), 1197 (s),
687 (w), 526 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 0.81–1.02 (m, 1 H, CH2), 1.25–
1.63 (m, 12 H, CH2), 1.63–1.94 (m, 3 H, CH2), 2.46–2.58 (m, 2 H,
CH2), 2.58–2.70 (m, 2 H, CH2).
13C NMR (75 MHz, CDCl3): d = 23.2, 23.5, 23.6, 25.6, 26.3, 26.8,
27.1, 27.2, 27.5, 29.3 (CH2), 119.9, 144.6 (C), 160.6 (CN), 164.6
(CO).
MS (EI, 70 eV): m/z (%) = 251 (M+, 19), 206 (100), 178 (86), 154
(13), 141 (12), 136 (29), 122 (16), 95 (17).
HRMS (EI, 70 eV): m/z (M+) calcd for C14H21NO3: 251.1516;
found: 251.1512.
Ethyl 3-(2-Methylphenyl)isoxazole-5-carboxylate (4d)
Starting from 3d (0.105 g, 0.407 mmol) in toluene (20 mL) and us-
ing TsOH·H2O (0.405 g, 2.1 mmol) gave 4d as a brownish oil; yield:
0.091 g (96%).
Synthesis 2006, No. 15, 2515–2522 © Thieme Stuttgart · New York

2520
T. T. Dang et al.
PAPER
IR (KBr): 3428 (w), 2988 (w), 1723 (s), 1447 (s), 1292 (s), 1278 (s),
1024 (m), 768 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 1.35 (t, 3J = 7.2 Hz, 3 H,
OCH2CH3), 2.41 (s, 3 H, CH3), 4.35 (q, 3J = 7.2 Hz, 2 H,
OCH2CH3), 7.25 (s, 1 H, CH), 7.32 (m, 3 H, Ar), 7.53 (d, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH2CH3), 62.6 (OCH2CH3),
110.6 (CH), 125.6, 125.6, 126.9, 127.8, 128.2, 128.5, 131.2 (CH,
Ar), 125.1, 130.7, 133.8 (C, Ar), 156.9 (C), 160.3 (CN), 163.1 (CO).
MS (EI, 70 eV): m/z (%) = 267 (M+, 74), 194 (100), 174 (19), 166
(33), 127 (59), 109 (15), 81 (9), 77 (14), 69 (7).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH2CH3), 21.1 (CH3), 62.2
(OCH2CH3), 109.9 (CH), 126.1, 129.8, 130.4, 131.6 (CH, Ar),
127.6,136.9 (C, Ar), 156.8 (C), 161.3 (CN), 163.5 (CO).
HRMS (EI, 70 eV): m/z (M+) calcd for C16H13NO3: 267.0890;
found: 267.0895.
Ethyl 3-(2-Naphthyl)isoxazole-5-carboxylate (4h)
Starting from 3h (0.173 g, 0.60 mmol) in toluene (20 mL) and using
TsOH·H2O (0.574 g, 3.0 mmol) gave 4h as a black oil; yield: 0.122
g (76%).
MS (EI, 70 eV): m/z (%) = 231 (M+, 76), 186 (8), 158 (100), 130
(96), 116 (15), 103 (39), 91 (49.5), 77 (20), 65 (40).
HRMS (EI, 70 eV): m/z (M+) calcd for C13H13NO3: 231.0889;
found: 231.0883.
IR (KBr): 3433 (w), 2978 (w), 1727 (s), 1431 (m), 1290 (s), 1253
(s), 1026 (m), 822 (m), 753 (m), 476 cm–1 (m).
Ethyl 3-(4-Methoxyphenyl)isoxazole-5-carboxylate (4e)
Starting from 3e (0.349 g, 1.31 mmol) in toluene (30 mL) and using
TsOH·H2O (1.23 g, 6.47 mmol) gave 4e as a brownish oil; yield:
0.219 g (68%).
3
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.1 Hz, 3 H, CH3),
4.40 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 7.35 (s, 1 H, CH), 7.53 (m, 2
H, Ar), 7.97 (m, 4 H, Ar), 8.37 (m, 1 H, Ar).
IR (KBr): 3442 (w), 2979 (w), 1731 (s), 1454 (s), 1282 (s), 1252 (s),
1031 (m), 766 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 1.35 (t, 3J = 7.2 Hz, 3 H,
OCH2CH3), 3.85 (s, 3 H, OCH3), 4.35 (q, 3J = 7.2 Hz, 2 H,
OCH2CH3), 7.05 (d, 2 H, ArH), 7.25 (s, 1 H, CH), 7.71 (d, 2 H, Ar).
13C NMR (75 MHz, CDCl3): d = 14.7 (CH2CH3), 62.7 (OCH2CH3),
107.9 (CH), 123.9, 125.4, 127.3, 128.0, 128.2, 129.0, 129.7 (CH,
Ar), 125.4, 133.3, 134.8 (C, Ar), 157.0 (C), 160.3 (CN), 163.1 (CO).
MS (EI, 70 eV): m/z (%) = 267 (M+, 94), 194 (100), 174 (14), 166
(56), 127 (79), 107 (5), 91 (5), 77 (14), 69 (13).
13C NMR (75 MHz, CDCl3): d = 13.1 (CH2CH3), 54.3 (OCH3), 62.6
(OCH2CH3), 107.5 (CH), 113.4, 127.2 (CH, Ar), 118.6, 154.7 (C,
Ar), 158.5 (C), 159.3 (CN), 160.4 (CO).
HRMS (EI, 70 eV): m/z (M+) calcd for C16H13NO3: 267.0890;
found: 267.0892.
Ethyl 3-(4-Chlorophenyl)isoxazole-5-carboxylate (4i)
Starting from 3i (0.108 g, 0.40 mmol) in toluene (20 mL) and using
TsOH·H2O (0.405 g, 2.1 mmol) gave 4i as a brownish solid; yield:
0.075 g (74%).
MS (EI, 70 eV): m/z (%) = 247 (M+, 10), 202 (4), 174 (100), 146
(88.5), 131 (12), 103 (6), 91 (3), 77 (8), 69 (12).
HRMS (EI, 70 eV): m/z (M+) calcd for C13H13NO4: 247.0839;
found: 247.0833.
IR (KBr): 3443 (w), 3132 (w), 1728 (s), 1448 (w), 1284 (s), 1246(s),
1023 (w), 926 (w), 828 (s), 761 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 1.35 (t, 3J = 7.2 Hz, 3 H,
OCH2CH3), 4.35 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 7.25 (s, 1 H, CH),
7.35 (d, 2 H, Ar), 7.71 (d, 2 H, Ar).
Ethyl 3-(3-Methoxyphenyl)isoxazole-5-carboxylate (4f)
Starting from 3f (0.349 g, 1.31 mmol) in toluene (30 mL) and using
TsOH·H2O (1.29 g, 6.79 mmol) gave 4f as a brownish oil; yield:
0.243 g (75%).
IR (KBr): 3447 (w), 2977 (w), 1736 (s), 1452 (s), 1285 (s), 1252 (s),
1033 (m), 761 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 1.35 (t, 3J = 7.2 Hz, 3 H,
OCH2CH3), 3.85 (s, 3 H, OCH3), 4.35 (q, 3J = 7.2 Hz, 2 H,
OCH2CH3), 7.25 (s, 1 H, CH), 7.42 (m, 2 H, Ar), 7.05 (m, 1 H, Ar),
7.38 (m, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH2CH3), 55.3 (OCH3), 62.3
(OCH2CH3), 107.4 (CH), 111.7, 116.6, 119.3, 130.1 (CH, Ar),
127.5, 156.7 (C, Ar), 160.0 (C), 160.8 (CN), 162.8 (CO).
MS (EI, 70 eV): m/z (%) = 247 (M+, 32), 202 (10), 174 (100), 146
(38), 131 (8), 107 (75), 92 (56), 77 (68), 69 (18).
HRMS (EI, 70 eV): m/z (M+) calcd for C13H13NO4: 247.0839;
found: 247.0837.
13C NMR (75 MHz, CDCl3): d = 14.1 (CH2CH3), 62.4 (OCH2CH3),
107.1 (CH), 128.1, 128.1, 129.4, 129.4 (CH, Ar), 126.3, 136.5 (C,
Ar), 157.1 (CN), 161.3 (C), 163.3 (CO).
MS (EI, 70 eV): m/z (%) = 251 (M+, 33), 178 (100), 150 (33), 138
(5), 111 (10), 75 (15), 63 (2).
HRMS (CI): m/z (M+) calcd for C12H10ClNO3: 251.0339; found:
251.0339.
Ethyl 3-(4-Fluorophenyl)isoxazole-5-carboxylate (4j)
Starting from 3j (0.126 g, 0.50 mmol) in toluene (20 mL) and using
TsOH·H2O (0.405 g, 2.1 mmol) gave 4j as a brownish solid; yield:
0.093 g (79%).
IR (KBr): 3443 (w), 3132 (w), 1728 (s), 1448 (w), 1284 (s), 1246
(s), 1023 (w), 926 (w), 828 (s), 761 cm–1 (m).
Ethyl 3-(1-Naphthyl)isoxazole-5-carboxylate (4g)
Starting from 3g (0.171 g, 0.60 mmol) in toluene (20 mL) and using
TsOH·H2O (0.574 g, 3.0 mmol) gave 4g as a black oil; yield: 0.131
g (82%).
1H NMR (300 MHz, CDCl3): d = 1.35 (t, 3J = 7.2 Hz, 3 H,
OCH2CH3), 4.35 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 7.25 (s, 1 H, CH),
7.25 (m, 2 H, Ar), 7.84 (m, 2 H, Ar).
13C NMR (75 MHz, CDCl3): d = 14.7 (CH2CH3), 62.4 (OCH2CH3),
107.2 (CH), 116.6, 116.8 (3J = 4.2 Hz, CH, Ar), 129.4, 129.4 (CH,
Ar), 124.3 (C, Ar), 163.9 (d, 1J = 250.8 Hz, CF), 161.2 (C), 156.8.5
(CN), 162.2 (CO).
IR (KBr): 3436 (w), 2985 (w), 1734 (s), 1445 (w), 1285 (s), 1026
(w), 919 (w), 775 (m), 656 cm–1 (w).
3
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.1 Hz, 3 H, CH3),
4.40 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 7.25 (s, 1 H, CH), 7.51 (m, 3
MS (EI, 70 eV): m/z (%) = 235 (M+, 71), 162 (100), 134 (77), 121
H, Ar), 7.70 (m, 1 H, Ar), 7.92 (m, 2 H, Ar), 8.34 (m, 1 H, Ar).
(10), 107 (18), 95 (19), 81 (3), 75 (11).
HRMS (EI, 70 eV): m/z (M+) calcd for C12H10FNO3: 235.0639;
found: 235.0638.
Synthesis 2006, No. 15, 2515–2522 © Thieme Stuttgart · New York

PAPER
Isoxazole-5-carboxylates by Cyclization of Oxime 1,4-Dianions with Diethyl Oxalate
2521
3
Ethyl 3-[3-(Trifluoromethyl)phenyl]isoxazole-5-carboxylate
(4k)
Starting from 3k (0.152 g, 0.50 mmol) in toluene (20 mL) and using
TsOH·H2O (0.405 g, 2.1 mmol) gave 4k a brownish solid; yield:
0.121 g (85%).
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.1 Hz, 3 H, CH3),
1.25–1.58 (m, 12 H, CH2), 1.71–2.92 (m, 4 H, CH2), 2.62–2.77 (m,
4 H, CH2), 4.34 (q, 3J = 7.1 Hz, 2 H, OCH2CH3).
13C NMR (75 MHz, CDCl3): d = 14.0 (CH2CH3), 20.0, 21.5, 22.4,
22.7, 24.1, 24.5, 25.5, 25.8, 26.9, 27.3 (CH2), 61.8 (OCH2CH3),
125.5, 154.8 (C), 157.5 (CN), 165.0 (CO).
IR (KBr): 3435 (w), 3126 (w), 1727 (s), 1423 (w), 1278 (s), 1246
(s), 1023 (w), 910 (w), 819 (s), 770 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 1.35 (t, 3J = 7.2 Hz, 3 H,
OCH2CH3), 4.35 (q, 3J = 7.2 Hz, 2 H, OCH2CH3), 7.25 (s, 1 H, CH),
7.62 (m, 1 H, Ar), 7.83 (d, 1 H, Ar), 8.12 (m, 2 H, Ar).
MS (EI, 70 eV): m/z (%) = 279 (M+, 11), 206 (100), 178 (11), 150
(4), 136 (6), 121 (2), 108 (4), 95 (6).
HRMS (EI, 70 eV): m/z (M+) calcd for C16H25NO3: 279.1829;
found: 279.1824.
13C NMR (75 MHz, CDCl3): d = 14.5 (CH2CH3), 62.9 (OCH2CH3),
3
106.6 (CH), 123.6 (q, 3J = 3.5 Hz, CH, Ar), 127.1(q, J = 3.5 Hz,
6,7,8,9-Tetrahydro-4-hydroxycyclohept[c][1,2]oxazin-3(5H)-
one (5p)
Starting from a soln of oxime 1p (0.271 g, 2.0 mmol) in THF (20
mL) and using 2.5 M n-BuLi in hexane (2.0 mL, 2.5 mmol) and di-
ethyl oxalate (0.3 mL, 2.2 mmol) gave 5p as a pink solid; yield:
0.171 g (47%); mp 154 °C.
CH, Ar), 129.4, 130.2 (CH, Ar), 124.3 (q, 1J = 272.3 Hz, CF), 129.1
(C), 131.7 (q, 2J = 32.8 Hz, C), 156.1 (CN), 161.3 (CO).
MS (EI, 70 eV): m/z (%) = 285 (M+, 24), 212 (100), 171 (2), 145
(13), 121 (1), 75 (6).
HRMS (CI): m/z (M+) calcd for C13H10F3NO3: 285.0607; found:
285.0603.
IR (KBr): 3188 (m), 2937 (m), 1718 (s), 1656 (m), 1385 (m), 1243
(w), 1177 (w), 1097 (w), 806 cm–1 (m).
Ethyl 4,5-Dihydronaphtho[1,2-c]isoxazole-3-carboxylate (4n)
Starting from 3n (0.302 g, 1.15 mmol) in toluene (30 mL) and using
TsOH·H2O (1.14 g, 6.0 mmol) gave 4n as a black solid; yield: 0.254
g (91%); mp 181 °C.
1H NMR (300 MHz, CDCl3): d = 1.42–1.85 (m, 6 H, CH2), 2.62–
2.81 (m, 4 H, CH2), 7.12 (br s, OH).
13C NMR (75 MHz, CDCl3): d = 25.2, 27.2, 27.9, 31.3, 33.6 (CH2),
120.5, 142.5 (C), 162.4 (CN), 164.4 (CO).
IR (KBr): 3438 (w), 2928 (w), 1712 (s), 1641 (w), 1454 (s), 1369
(s), 1268 (s), 1174 (m), 783 (w), 716 (w), 687 cm–1 (w).
MS (EI, 70 eV): m/z (%) = 181 (M+, 19), 136 (100), 107 (29), 94
(9.9), 81 (76), 55 (46), 41 (52), 39 (29), 28 (37).
3
1H NMR (300 MHz, CDCl3): d = 1.45 (t, J = 7.1 Hz, 3 H, CH3),
Anal. Calcd for C9H11NO3: C, 59.66; H, 6.12; N, 7.73. Found: C,
59.71; H, 6.22; N, 7.46.
3
2.92–3.19 (m, 4 H, CH2), 4.43 (q, J = 7.2 Hz, 2 H, OCH2CH3),
7.23–7.41 (m, 3 H, Ar), 8.02 (m, 1 H, Ar).
13C NMR (75 MHz, CDCl3): d = 14.2 (CH2CH3), 18.9, 28.2 (CH2),
61.9 (OCH2CH3), 121.4, 124.6 (C), 124.3, 127.2, 128.6, 130.4 (4
CH, Ar), 137.5, 154.2 (2 C, Ar), 157.4 (CN), 161.4 (CO).
MS (EI, 70 eV): m/z (%) = 243 (M+, 100), 198 (19), 170 (98), 143
(97), 127 (20), 115 (95), 89 (42), 77 (10), 69 (31).
HRMS (EI, 70 eV): m/z (M+) calcd for C14H13NO3: 243.0890;
found: 243.0881.
5,6,7,8,9,10-Hexahydro-4-hydroxy-3H-cyclooct[c][1,2]oxazin-
3-one (5q)
Starting from a soln of oxime 1q (0.283 g, 2.0 mmol) in THF (20
mL) and using 2.5 M n-BuLi in hexane (2.0 mL, 5.0 mmol) and di-
ethyl oxalate (0.3 mL, 2.2 mmol) gave 5q as an orange solid; yield:
0.152 g (39%); mp 98 °C.
IR (KBr): 3398 (m), 3291 (m), 2927 (m), 1703 (s), 1653 (w), 1189
(w), 1125 (w), 865 cm–1 (m).
Ethyl 4,5,6,7-Tetrahydro-2,1-benzisoxazole-3-carboxylate (4o)
Starting from 3o (0.358 g, 1.69 mmol) in toluene (30 mL) and using
TsOH·H2O (1.596 g, 8.4 mmol) gave 4o as a brownish oil; yield:
0.256 g (78%).
1H NMR (300 MHz, CDCl3): d = 1.41–1.63 (m, 4 H, CH2), 1.74–
1.91 (m, 4 H, CH2), 2.60–2.73 (m, 2 H, CH2), 2.73–2.82 (m, 2 H,
CH2), 7.56 (br s, OH).
13C NMR (75 MHz, CDCl3): d = 23.3, 25.5, 25.9, 27.8, 29.9, 30.5
(CH2), 119.9, 143.4 (C), 161.6 (CN), 164.6 (CO).
MS (EI, 70 eV): m/z (%) = 195 (M+, 4), 149 (35), 122 (16), 94 (32),
81 (16).
HRMS (EI, 70 eV): m/z (M+) calcd for C10H13NO3: 195.0895;
found: 195.0892.
IR (KBr): 2947 (m), 1716 (s), 1363 (m), 1290 (s), 1176 (s), 1038
(m), 917 (w), 769 cm–1 (w).
3
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 7.1 Hz, 3 H, CH3),
1.73–1.93 (m, 4 H, CH2), 2.74–2.91 (m, 4 H, CH2), 4.35 (q, 3J = 7.2
Hz, 2 H, OCH2CH3).
13C NMR (75 MHz, CDCl3): d = 14.0 (CH2CH3), 20.3, 21.4, 21.6,
21.7 (CH2), 61.6 (OCH2CH3), 122.6, 154.5 (C), 157.6 (CN), 161.9
(CO).
Acknowledgement
MS (EI, 70 eV): m/z (%) = 195 (M+, 4), 166 (11), 150 (17), 138 (18),
122 (81), 95 (57), 80 (99), 67 (77).
HRMS (EI, 70 eV): m/z (M+) calcd for C10H13NO3: 195.0890;
We are grateful to Dr. Dirk Michalik for NMR studies. Financial
support from the Ministry of Education of Vietnam (MOET schol-
arship for T.T.D.) is gratefully acknowledged.
found: 195.0893.
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Synthesis 2006, No. 15, 2515–2522 © Thieme Stuttgart · New York

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T. T. Dang et al.
PAPER
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Synthesis 2006, No. 15, 2515–2522 © Thieme Stuttgart · New York