A convenient synthesis of 4-substituted 3-ethoxy-5-methylisoxazoles by palladium-catalyzed coupling reactions

Article abstract of DOI:10.1016/S0040-4020(01)00052-7

The coupling reactions were performed using 3-ethoxy-4-iodo-5-methylisoxazole (4) as the key intermediate. Coupling of 4 under Suzuki-Miyaura or Stille conditions using Pd(PPh₃)₂Cl₂ and arylboronic acids or aryltin analogu

Full text of DOI:10.1016/S0040-4020(01)00052-7

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2195±2201
A convenient synthesis of 4-substituted 3-ethoxy-5-
methylisoxazoles by palladium-catalyzed coupling reactions
Hasse Kromann, Frank A. Slùk, Tommy N. Johansen and Povl Krogsgaard-Larsenp
Department of Medicinal Chemistry, NeuroScience PharmaBiotec Research Centre, The Royal Danish School of Pharmacy,
2 Universitetsparken, DK-2100 Copenhagen, Denmark
Received 25 September 2000; revised 7 December 2000; accepted 4 January 2001
AbstractÐThe coupling reactions were performed using 3-ethoxy-4-iodo-5-methylisoxazole (4) as the key intermediate. Coupling of 4
under Suzuki±Miyaura or Stille conditions using Pd(PPh3)2Cl2 and arylboronic acids or aryltin analogues, respectively, gave 4-aryl substi-
tuted isoxazoles in yields ranging from 49% for the 3-pyridyl analogue 14, to 96% for the 4-pyridyl analogue 12. Under Heck reaction
conditions using Pd(PPh3)2Cl2 and 4, analogues of 3-ethoxy-5-methylisoxazole containing vinylic or acetylenic groups in the 4-position were
synthesized in yields ranging from 58 to 98%. 3-Ethoxy-5-methylisoxazol-4-ylmagnesium bromide (19), prepared from 4 and isopropyl-
magnesium bromide, reacted smoothly with benzaldehyde or benzoyl chloride to give the desired 4-[hydroxy(phenyl)methyl] analogue 21
and 4-benzoyl-3-ethoxy-5-methylisoxazole (22), respectively. Transmetallation of 19 with ZnCl2 and subsequent treatment with
Pd(PPh3)2Cl2 and 4-iodotoluene gave 3-ethoxy-5-methyl-4-(4-methylphenyl)isoxazole (23) in 80% yield. q 2001 Elsevier Science Ltd.
All rights reserved.
1. Introduction
we decided to develop a method for the synthesis of ana-
logues of 2 containing aryl or heteroaryl substituents in the
4-position of the 3-isoxazolol ring.
The central excitatory neurotransmitter (S)-glutamic acid
(Glu) operates through ionotropic Glu receptors (iGluRs),
subdivided into N-methyl-d-aspartic acid (NMDA), (RS)-2-
amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid
(AMPA), and kainic acid receptors, as well as metabotropic
Glu receptors (mGluRs) of which eight receptor subtypes
are known.1±3 All of these receptors are potential thera-
peutic targets, and the ®rst step in the development of Glu
receptor subtype-selective drugs on a rational basis is the
design of subtype-selective receptor ligands (Fig. 1).
The classical method of synthesizing 4,5-disubstituted
3-isoxazolols is based on reaction of hydroxylamine with
appropriately substituted b-ketoesters, but these reactions
inherently provide 3-isoxazolols as well as the isomeric
3-isoxazolin-5-ones in ratios dependent on the structures
of the b-ketoesters and the reaction conditions.9,10 Recently,
a method for the synthesis of 3-isoxazolols without for-
mation of 3-isoxazolin-5-ones, based on reaction of
5-acylated Meldrum's acids with O,N-diprotected hydroxyl-
amine, was reported,11 but none of these methods have
Analogues of (S)-AMPA (1) containing different alkyl or, in
particular, aryl and heteroaryl substituents in the 5-position
of the 3-isoxazolol ring have played a key role in the develop-
ment of the pharmacology of the AMPA-receptor.4±6 In
contrast to (S)-AMPA (1), the isomeric 3-isoxazolol
amino acid (S)-2-amino-3-(3-hydroxy-4-methylisoxazol-5-
yl)propionic acid [(S)-4-Me-homoibotenic acid (2)] inter-
acts with AMPA receptors as well as with mGluR subtypes.7
Replacement of the methyl group of 2 with more bulky
nonaromatic substituents has been shown to enhance the
selectivity of these analogues for mGluRs.7,8 In light of
these observations and the results of structure±activity
studies on 5-aryl substituted analogues of (S)-AMPA (1),
Keywords: 3-hydroxy-5-methylisoxazole; cross-coupling; palladium cata-
lyzed; Stille; Suzuki±Miyaura; Heck.
p
Corresponding author. Tel.: 145-353-06511; fax: 145-353-06040;
e-mail: ano@dfh.dk
Figure 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00052-7

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H. Kromann et al. / Tetrahedron 57 (2001) 2195±2201
Table 2. Suzuki±Miyaura and Stille reactions of 3-ethoxy-4-iodo-5-methyl-
isoxazole (4)
Scheme 1.
R
Product
Yield (%)
proved useful for the synthesis of 3-isoxazolols linked
directly to aryl or heteroaryl ring systems in the 4-position.
In the light of these synthetic limitations, we have been
working on the development of methods and conditions
for direct coupling between C-4 of O-protected and
5-substituted 3-isoxazolols and different aromatic or hetero-
aromatic rings.
Ph
6
7
8
84
85
88
80
76
90
96
92
49
1-Naphthyl
2-Naphthyl
2-Ph-OCH3
3-Ph-OCH3
4-Ph-OCH3
4-Pyridyl
2-Pyridyl
3-Pyridyl
9
10
11
12
13
14
Transition metal-catalyzed coupling of organometallic
reagents with aryl halides or tri¯ates has been widely used
to form carbon±carbon bonds.12±15 Palladium-catalyzed
coupling reactions have been used for the formation of
4-aryl-3,5-dimethylisoxazole from 3,5-dimethyl-4-iodo-
isoxazole16 and for the formation of 4-aryl-3-methyl-
isoxazole from 4-(tributylstannyl)-3-methylisoxazole.17
Furthermore, direct phenylation of 4-unsubstituted
3-(p-toluenesulfonyloxy)isoxazole using either benzene or
phenyl iodide,18 and coupling of alkynes and alkenes with
3,5-dimethyl-4-iodoisoxazole using a palladium catalyst has
been reported.19
suitable intermediates for the synthesis of pharmaco-
logically interesting 3-isoxazolol-containing amino acids.
2. Results and discussion
3-Ethoxy-5-methylisoxazole (3)20 was converted into 4, in
80% yield, by treatment with iodine chloride in aqueous
acetic acid and into 5, in 64% yield, by treatment with
bromine in CCl4 (Scheme 1). Suzuki±Miyaura coupling
reactions between phenylboronic acid and 4 or 5 gave
3-ethoxy-5-methyl-4-phenylisoxazole (6), in 84 and 33%
isolated yields, respectively (Table 1, entries 2 and 3), the
former reaction showing complete conversion of starting
material after 18 h. Starting out with 4, but substituting
Ni(PPh3)2Cl2 for Pd(PPh3)2Cl2 under identical conditions
only gave 40% conversion of 4 (Table 1, entry 1). Although
the oxidation state of the palladium at the moment of the
reaction is not entirely clear,12,21±24 the coupling reactions
described here were performed using Pd(PPh3)2Cl2 without
the addition of any kind of reducing agents or addition
of triphenylphosphine, in agreement with the Suzuki±
Beletskaya procedure.22,23
To our knowledge, this is the ®rst report of palladium-
catalyzed coupling reactions affording 4-aryl and 4-hetero-
aryl substituted 3-alkoxyisoxazoles, compounds which are
Table 1. Reactions of 4-substituted alkoxyisoxazoles using Ni- or Pd-cata-
lysts
The Suzuki±Miyaura coupling reactions between 4 and the
boronic acid reagents were performed in a mixture of DME
and water using NaHCO3 as base (Table 2). The Stille
coupling reactions between 4 and the tributyltin reagents
were performed in toluene or DMF (Table 2). In order to
overcome problems with the separation of product from
tributylstannyl halide, the products were isolated via for-
mation of the hydrobromide salts.
Starting material
X
Catalyst
6:4/5a
4
4
5
I
I
Br
Ni(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
2:3
1:0
1:2
The palladium-catalyzed Heck reactions have been exten-
sively used for arylation and vinylation of ole®ns.25,26 The
reactions shown in Table 3 were performed under conditions
a
Product/starting material ratio as determined by NMR.

H. Kromann et al. / Tetrahedron 57 (2001) 2195±2201
Table 3. Heck reaction of 3-ethoxy-4-iodo-5-methylisoxazole (4)
2197
R1
R2
Product
Yield (%)
Ph
CN
COOCH3
±
±
±
±
Ph
15
16
17
18
91
77
98
58
described by Jeffery,27,28 using DMF as solvent, tetrabutyl-
ammonium bromide as the phase transfer reagent, and
K2CO3 as base.
into 21 and 22 by reaction with benzaldehyde and benzoyl
chloride, respectively (Scheme 2).
In conclusion, different palladium-catalyzed coupling reac-
tions have been effectively used for the incorporation of
aromatic, heteroaromatic, and vinylic or acetylenic groups
into the 4-position of compound 3. Furthermore, 4-substi-
tuted analogues of 3 have been synthesized via the Grignard
intermediate 19, formed by an iodine/magnesium exchange
reaction between compound 4 and isopropylmagnesium
bromide.
In Scheme 2, the incorporation of different functionalities
into the 4-position of compound 3 via metallation of this
position is outlined. In agreement with previous ®ndings,29
reactions of 3 with alkyllithium reagents primarily resulted
in deprotonation of the methyl group of the 5-position of 3.
Recently, iodine/magnesium exchange reactions between
alkylmagnesium halides and aryl iodides have been reported
for effective generation of arylmagnesium halides.30±36
Thus, compound 4 was effectively converted into the
Grignard intermediate 19, which was transmetallated with
ZnCl2 to give 20, and subsequent palladium-catalyzed reac-
tion of 20 with 4-iodotoluene gave 23 in good yield. The
heteroarylmagnesium bromide 19 was smoothly converted
These results have paved the way for the synthesis of ana-
logues of the 3-isoxazolol amino acid 2, in which the methyl
group has been replaced by different aromatic or unsaturated
groups. This group of compounds are predicted to be
interesting ligands for central Glu receptors.
Scheme 2.

2198
H. Kromann et al. / Tetrahedron 57 (2001) 2195±2201
3. Experimental
4-iodo-5-methylisoxazole (4). General procedure. To a
solution of compound 4 (1.0 g, 4.0 mmol) in DME
(10 mL) was added Pd(PPh3)2Cl2 (80 mg, 0.11 mmol). The
stirred mixture was left at rt for 15 min followed by addition
of water (10 mL), NaHCO3 (1.0 g, 12.0 mmol) and the
boronic acid (5.9 mmol). The reaction was stirred at 808C
overnight. The mixture was cooled to rt, and diethylether
(20 mL) was added. The two phases were separated, and the
organic phase was washed with water (10 mL), 2 M NaOH
(2£10 mL), and water (10 mL). Drying of the organic phase
(MgSO4), ®ltration, and concentration in vacuo gave the
crude product that was puri®ed by CC.
3.1. General
1H and associated proton test (APT) NMR spectra were
recorded on a 300 MHz Varian Gemini spectrometer,
using CDCl3 as the solvent. Chemical shifts are given in
ppm (d) using TMS as the internal standard, and coupling
constants (J) are given in Hertz. Column chromatography
(CC) was performed on Merck silica gel 60 (0.063±
0.200 mm). Compounds were visualized on TLC (silica
gel 60 F254 plates, Merck) using UV light and KMnO4
spraying reagent. All reactions involving air-sensitive
reagents were performed under N2. Melting points were
determined in open capillaries and are uncorrected. All
solvents and reagents were obtained from Fluka, Aldrich,
or Maybridge and used without further puri®cation, except
THF which was distilled from Na/benzophenone ketyl
3.1.4. 3-Ethoxy-5-methyl-4-phenylisoxazole (6). CC
(hexane/EtOAc 20:1, 1% AcOH) gave 6 (84%) as white
1
crystals: mp 46±47.58C, H NMR d 1.45 (t, Jˆ6.9 Hz,
3H), 2.45 (s, 3H), 4.40 (q, Jˆ7.2 Hz, 2H), 7.43±7.45 (m,
5H), 13C NMR d 12.46, 14.45, 65.64, 106.87, 127.20,
128.28, 128.57, 129.12, 166.03, 169.54. Anal. Calcd for
C12H13O2N: C, 70.92, H, 6.45, N, 6.89. Found: C, 71.15,
H, 6.74, N, 6.90.
Ê
under N2, and DMF which was stored over 3 A molecular
sieves. The anisolboronic acids,37 2-naphthaleneboronic
acid,38 4-pyridineboronic acid,39 and 2-(tributylstannyl)-
pyridine40 were prepared as previously described. A solu-
tion of ZnCl2 in THF was prepared by ¯ame-drying ZnCl2 in
vacuo and dissolving it in dry THF. A solution of iso-
propylmagnesium bromide in THF was prepared as
previously described.41 Elemental analyses were performed
at Analytical Research Department, H. Lundbeck A/S,
Denmark or by J. Theiner, Microanalytical Laboratory, Insti-
tute of Physical Chemistry, University of Vienna, Austria.
3.1.5. 3-Ethoxy-4-(1-naphthyl)-5-methylisoxazole (7). CC
(toluene, 1% AcOH) gave 7 (85%) as orange crystals.
Recrystallization (diethylether/hexane) gave white crystals:
1
mp 83±858C, H NMR d 1.31 (t, Jˆ7.0 Hz, 3H), 2.24 (s,
3H), 4.35 (q, Jˆ7.0 Hz, 2H), 7.36±7.94 (m, 7H), 13C NMR
d 12.14, 14.44, 65.68, 106.02, 125.44, 125.62, 126.06,
126.21, 126.24, 128.48, 128.65, 128.73, 132.16, 133.85,
167.58, 170.32. Anal. Calcd for C16H15NO2: C, 75.87, H,
5.97, N, 5.53. Found: C, 75.99, H, 5.97, N, 5.57.
Accurate mass determinations (^2 ppm) were performed at
the University of Southern Denmark, Odense University,
Department of Chemistry, on an IonSpec Fourier Transform
Mass Spectrometer, using matrix assisted laser desorption
ionization (MALDI) with 2,5-dihydroxybenzoic acid as
matrix.
3.1.6. 3-Ethoxy-4-(2-naphthyl)-5-methylisoxazole (8). CC
(toluene, 1% AcOH) gave 8 (88%) as orange crystals.
Recrystallization (diethylether/hexane) gave white crystals:
1
mp 39±408C, H NMR d 1.39 (t, Jˆ7.0 Hz, 3H), 2.44 (s,
3H), 4.35 (q, Jˆ7.0 Hz, 2H), 7.48 (dd, Jˆ8.5, 1.8 Hz, 1H),
7.40±7.45 (m, 2H), 7.75±7.84 (m, 3H), 7.80 (s, 1H), 13C
NMR d 12.68, 14.57, 65.80, 107.07, 126.19, 126.32,
126.37, 126.65, 127.36, 127.74, 127.98, 128.25, 132.44,
133.45, 166.37, 169.77. Anal. Calcd for C16H15NO2: C,
75.87, H, 5.97, N, 5.53. Found: C, 75.77, H, 6.05, N, 5.52.
3.1.1. 3-Ethoxy-4-iodo-5-methylisoxazole (4). To a solu-
tion of compound 320 (8.0 g, 63 mmol) in AcOH (250 mL)
and water (300 mL) was added iodine chloride (12.2 g,
75 mmol). The stirred solution was heated to 808C for
2.5 h, and was cooled to rt. The solution was added to a
10% solution of Na2SO3 in water (50 mL) and water
(250 mL), and the white precipitate was ®ltered off and
redissolved in acetone (200 mL). Impurities were ®ltered
off and to the ®ltrate was added water (800 mL) giving
white crystals (12.8 g, 80%). Recrystallization (hexane)
3.1.7. 3-Ethoxy-4-(2-methoxyphenyl)-5-methylisoxazole
(9). CC (toluene, 1% AcOH) gave 9 (80%) as white crystals:
1
mp 58±598C, H NMR d 1.38 (t, Jˆ7.0 Hz, 3H), 2.27 (s,
3H), 3.82 (s, 3H), 4.33 (q, Jˆ7.0 Hz, 2H), 6.97 (dd, Jˆ8.0,
0.6 Hz, 1H), 7.01 (ddd, Jˆ7.4, 7.4, 1.1 Hz, 1H), 7.25 (dd,
Jˆ7.5, 1.8 Hz, 1H), 7.34 (ddd, Jˆ8.0, 7.4, 1.8 Hz, 1H), 13C
NMR d 12.70, 14.53, 55.32, 65.45, 103.57, 111,19, 117.67,
120.57, 129.33, 131.53, 157.14, 167.47, 170.03. Anal. Calcd
for C13H15NO3: C, 66.94, H, 6.48, N, 6.00. Found C, 67.18,
H, 6.52, N, 5.95.
1
gave 4 as white crystals: mp 56.5±57.58C, H NMR d
1.44 (t, Jˆ7.2 Hz, 3H), 2.37 (s, 3H), 4.32 (q, Jˆ7.2 Hz,
2H), 13C NMR d 12.84, 14.37, 49.42, 66.24, 170.98,
171.12. Anal. Calcd for C6H8NO2I: C, 28.48, H, 3.19, N,
5.53. Found: C, 28.59, H, 3.19, N, 5.56.
3.1.2. 4-Bromo-3-ethoxy-5-methylisoxazole (5). To a
solution of compound 3 (2.4 g, 18.9 mmol) in CCl4
(30 mL) was added Br2 (3.3 g, 20.8 mmol), and the reaction
was left for 3 h at rt and subsequently concentrated in vacuo.
CC (toluene/EtOAc 9:1, 1% AcOH) gave 5 as a brown oil
(2.5 g, 64%) that turned black on standing: 1H NMR d 1.45
(t, Jˆ7.5 Hz, 3H), 2.34 (s, 3H), 4.34 (q, Jˆ7.5 Hz, 2H), 13C
NMR d 11.75, 14.31, 66.17, 82.68, 167.51, 168.69.
3.1.8. 3-Ethoxy-4-(3-methoxyphenyl)-5-methylisoxazole
(10). CC (toluene, 1% AcOH) gave 10 (76%) as a yellow
oil: 1H NMR d 1.44 (t, Jˆ6.9 Hz, 3H), 2.54 (s, 3H), 3.84 (s,
3H), 4.37 (q, Jˆ7.2 Hz, 2H), 6.87 (ddd, Jˆ8.4, 2.7, 1.2 Hz,
1H), 7.00±7.03 (m, 2H), 7.34 (dd, Jˆ8.1, 8.1 Hz, 1H), 13C
NMR d 12.68, 14.56, 55.17, 65.73, 106.82, 112.61, 114.20,
120.72, 129.67, 130.51, 159.77, 166.25, 169.60. HRMS
(MALDI): C13H15NO3 requires [M1H]1 at m/z 234.1125,
found 234.1127.
3.1.3. Palladium-catalyzed Suzuki coupling of 3-ethoxy-

H. Kromann et al. / Tetrahedron 57 (2001) 2195±2201
2199
3.1.9. 3-Ethoxy-4-(4-methoxyphenyl)-5-methylisoxazole
(11). CC (toluene, 1% AcOH) gave 11 (90%) as orange
crystals. Recrystallization (hexane) gave yellow crystals:
4-iodo-5-methylisoxazole (4) with vinylic compounds.
General procedure. A stirred mixture of 4 (1.0 g,
4.0 mmol), the vinylic compound (7.9 mmol), N(Bu)4Br
(1.3 g, 4.0 mmol), K2CO3 (1.4 g, 9.9 mmol) and
Pd(PPh3)2Cl2 (55 mg, 0.08 mmol) in DMF (10 mL) was
heated for 16 h at 608C followed by ®ltration and concen-
tration in vacuo. The black oil was redissolved in diethyl-
ether (40 mL) and water (40 mL), and the organic phase was
washed twice with water. Drying of the organic phase
(MgSO4), ®ltration and concentration in vacuo gave the
crude product that was puri®ed by CC.
1
mp 38±398C, H NMR d 1.43 (t, Jˆ7.0 Hz, 3H), 2.42 (s,
3H), 3.84 (s, 3H), 4.37 (q, Jˆ7.0 Hz, 2H,), 6.97 (d, Jˆ
8.8 Hz, 2H), 7.35 (d, Jˆ8.8 Hz, 2H), 13C NMR d 12.49,
14.56, 55.23, 65.64, 106.59, 114.14, 121.45, 129.59,
158.89, 165.45, 169.70. Anal. Calcd for C13H15NO3: C,
66.94, H, 6.48, N, 6.00. Found: C, 66.74, H, 6.32, N, 5.94.
3.1.10. 3-Ethoxy-5-methyl-4-(4-pyridyl)isoxazole (12).
CC (toluene, 1% AcOH) gave 12 (96%) as white crystals.
Recrystallization (diethylether/hexane) gave white crystals:
3.1.14. 3-Ethoxy-5-methyl-4-trans-styrylisoxazole (15).
CC (toluene, 1% AcOH) gave 15 (91%) as slightly orange
crystals. Recrystallization (hexane) gave white crystals: mp
1
mp 90±918C, H NMR d 1.47 (t, Jˆ7.1 Hz, 3H), 2.53 (s,
3H), 4.40 (q, Jˆ7.1 Hz, 2H), 7.41 (dd, Jˆ4.5, 1.6 Hz, 2H),
8.64 (dd, Jˆ4.6, 1.5 Hz, 2H), 13C NMR d 12.99, 14.37,
65.95, 104.54, 122.07, 137.19, 150.04, 167.67, 169.20.
Anal. Calcd for C11H12N2O2: C, 64.69, H, 5.92, N, 13.72.
Found: C, 64.75, H, 6.07, N, 13.63.
1
79.5±80.58C, H NMR d 1.49 (t, Jˆ7.0 Hz, 3H), 2.41 (s,
3H), 4.39 (q, Jˆ7.1 Hz, 2H), 6.67 (d, Jˆ16.5 Hz, 1H), 7.13
(d, Jˆ16.6 Hz, 1H), 7.24 (dd, Jˆ7.3, 7.3 Hz, 1H), 7.34 (dd,
Jˆ7.7, 7.1 Hz, 2H), 7.45 (d, Jˆ7.4 Hz, 2H), 13C NMR d
11.93, 14.58, 65.79, 104.73, 114.87, 126.14, 127.54, 128.68,
129.52, 137.61, 166.48, 169.90. Anal. Calcd for C14H15NO2:
C, 73.34, H, 6.59, N, 6.11. Found: C, 73.12, H, 6.50, N, 6.06.
3.1.11. Palladium-catalyzed Stille coupling of 3-ethoxy-
4-iodo-5-methylisoxazole (4); 3-ethoxy-5-methyl-4-(2-
pyridyl)isoxazole (13). To a solution of compound 4
(3.0 g, 11.9 mmol) in toluene (50 mL) was added
Pd(PPh3)2Cl2 (164 mg, 0.23 mmol), and the mixture was
left at rt for 15 min. 2-(Tributylstannyl)pyridine (6.3 g,
17.1 mmol) was added, and the reaction was left at 808C
for 16 h. The solution was concentrated in vacuo followed
by CC (toluene, 1% AcOH). The resulting crystals were
dissolved in EtOAc (30 mL) and cooled on ice. 33% HBr
in AcOH (3 mL) was added dropwise, and the white pre-
cipitate was ®ltered of and washed with EtOAc, dried and
added to water (50 mL). The aqueous suspension was
neutralized using saturated NaHCO3 (25 mL) to neutral
pH and was extracted with EtOAc (3£50 mL). The organic
layers were dried (MgSO4) and concentrated in vacuo to
give yellow crystals (2.4 g, 92%). Recrystallization
(heptane) gave 13 as white crystals: mp 48±498C, 1H
NMR d 1.49 (t, Jˆ7.2 Hz, 3H), 2.71 (s, 3H), 4.44 (q,
Jˆ7.2 Hz, 2H), 7.15 (dd, Jˆ7.4, 5.0 Hz, 1H), 7.70 (dd,
Jˆ7.4, 7.4 Hz, 1H), 7.75 (d, Jˆ8.0 Hz, 1H), 8.61 (d, Jˆ
4.9 Hz, 1H), 13C NMR d 13.81, 14.58, 65.90, 105.97,
121.40, 122.09, 136.31, 149.38, 150.02, 169.39, 170.24.
Anal. Calcd for C11H12N2O2: C, 64.69, H, 5.92, N, 13.72.
Found: C, 64.78, H, 5.92, N, 13.72.
3.1.15. trans-3-(3-Ethoxy-5-methylisoxazol-4-yl)acrylo-
nitrile (16). CC (toluene, 1% AcOH) gave 16 (77%) as
yellow crystals. Recrystallization (diethylether) gave white
1
crystals: mp 111±111.58C, H NMR d 1.46 (t, Jˆ7.0 Hz,
3H), 2.42 (s, 3H), 4.37 (q, Jˆ7.0 Hz, 2H), 6.00 (d, Jˆ
16.5 Hz, 1H), 7.05 (d, Jˆ16.5 Hz, 1H), 13C NMR d 11.78,
14.39, 66.48, 96.31, 103.47, 118.39, 136.70, 169.43, 170.61.
Anal. Calcd for C9H10N2O2: C, 60.66, H, 5.66, N, 15.72.
Found: C, 60.85, H, 5.76, N, 15.81.
3.1.16. Methyl trans-3-(3-ethoxy-5-methylisoxazol-4-yl)-
acrylate (17). CC (toluene, 1% AcOH) gave 17 as orange
crystals (98%). Recrystallization (diethylether/hexane) gave
1
slightly orange crystals: mp 54.5±55.08C, H NMR d 1.47
(t, Jˆ7.0 Hz, 3H), 2.44 (s, 3H), 3.79 (s, 3H), 4.37 (q,
Jˆ7.0 Hz, 2H), 6.50 (d, Jˆ15.9 Hz, 1H), 7.37 (d, Jˆ
15.9 Hz, 1H), 13C NMR d 11.92, 14.50, 51.58, 66.19,
103.59, 117.85, 131.09, 167.81, 169.84, 170.63. Anal.
Calcd for C10H13NO4: C, 56.86, H, 6.20, N, 6.63. Found:
C, 56.80, H, 6.10, N, 6.45.
3.1.17. 3-Ethoxy-5-methyl-4-(phenylethynyl)isoxazole (18).
A stirred mixture of 4 (1.0 g, 4.0 mmol), phenylacetylene
(880 mL, 8.0 mmol), N(Bu)4Br (1.3 g, 4.0 mmol), K2CO3
(1.4 g, 9.9 mmol) and Pd(PPh3)2Cl2 (55 mg, 0.08 mmol) in
DMF (10 mL) was heated for 16 h at 608C followed by
®ltration and concentration in vacuo. The black oil was
redissolved in diethylether (40 mL) and water (40 mL)
and the organic phase was washed twice with water. Drying
of the organic phase (MgSO4), ®ltration, and concentration
in vacuo followed by CC (hexane/EtOAc 5:1, 1% AcOH)
gave 18 (530 mg, 58%) as a colourless oil: 1H NMR d 1.46
(t, Jˆ7.0 Hz, 3H), 2.44 (s, 3H), 4.35 (q, Jˆ7.0 Hz, 2H),
7.32±7.35 (m, 3H), 7.50±7.53 (m, 2H), 13C NMR d 12.45,
14.38, 66.14, 75.83, 92.43, 94.27, 122.81, 128.35, 128.53,
131.62, 170.40, 172.64. HRMS (MALDI): C14H13NO2
requires [M1Na]1 at m/z 250.0839, found 250.0838.
3.1.12. 3-Ethoxy-5-methyl-4-(3-pyridyl)isoxazole (14).
To a solution of compound 4 (3.0 g, 11.9 mmol) in DMF
(50 mL), was added Pd(PPh3)2Cl2 (164 mg, 0.23 mmol),
and the solution was left at rt for 15 min. 3-(Tributyl-
stannyl)pyridine (6.3 g, 17.1 mmol) was added, and the
reaction mixture was left at 808C for 16 h. Workup as
described above for compound 13. Yield: 49% as white
crystals. Recrystallization (hexane) gave 14 as white crys-
tals: mp 81±828C, 1H NMR d 1.45 (t, Jˆ7.2 Hz, 3H), 2.50
(s, 3H), 4.40 (q, Jˆ6.9 Hz, 2H), 7.44 (dd, Jˆ8.1, 4.8 Hz,
1H), 7.86 (ddd, Jˆ8.1, 2.1, 1.8 Hz, 1H), 8.58 (d, Jˆ3.9 Hz,
1H), 8.72 (bs, 2H), 13C NMR d 12.74, 14.49, 66.08, 103.66,
123.92, 126.10, 136.33, 147.18, 147.90, 167.05, 169.36.
Anal. Calcd for C11H12N2O2: C, 64.69, H, 5.92, N, 13.72.
Found: C, 64.80, H, 5.94, N, 13.54.
3.1.18. (RS)-3-Ethoxy-4-[hydroxy(phenyl)methyl]-5-
methylisoxazole (21). To a solution of compound 4
3.1.13. Palladium-catalyzed Heck coupling of 3-ethoxy-

2200
H. Kromann et al. / Tetrahedron 57 (2001) 2195±2201
2. Metabotropic Glutamate Receptors and Brain Function,
Moroni, F., Nicoletti, F., Pellegrini-Giampietro, D. E., Eds.;
Portland: London, 1998.
(1.0 g, 4.0 mmol) in THF (20 mL), cooled to 2308C, was
dropwise added 2.0 M isopropylmagnesium bromide in
THF (2.5 mL, 4.9 mmol). The reaction mixture was heated
to 08C and left for 1 h followed by addition of benzaldehyde
(400 mL, 4.0 mmol). The reaction was heated to rt and left
overnight followed by addition of a saturated solution of
NH4Cl in water (20 mL). The organic phase was washed
with water, dried (MgSO4), ®ltered, and concentrated in
vacuo. CC (toluene, 1% AcOH) gave 21 as white crystals
(760 mg, 82%). Recrystallization (diethylether/hexane)
È
3. Brauner-Osborne, H.; Egebjerg, J.; Nielsen, E. é.; Madsen,
U.; Krogsgaard-Larsen, P. J. Med. Chem. 2000, 43, 2609±
2645.
4. Ebert, B.; Lenz, S. M.; Brehm, L.; Bregnedal, P.; Hansen, J. J.;
Frederiksen, K.; Bùgesù, K. P.; Krogsgaard-Larsen, P. J. Med.
Chem. 1994, 37, 878±884.
5. Bang-Andersen, B.; Lenz, S. M.; Skjñrbñk, N.; Sùby, K. K.;
Hansen, H. O.; Ebert, B.; Bùgesù, K. P.; Krogsgaard-Larsen,
P. J. Med. Chem. 1997, 40, 2831±2842.
1
gave white crystals: mp 79.5±818C, H NMR d 1.35 (t, Jˆ
7.0 Hz, 3H), 2.12 (s, 3H), 3.03 (d, Jˆ4.8 Hz, 1H), 4.25 (q,
Jˆ7.0 Hz, 2H), 5.68 (d, Jˆ4.7 Hz, 1H), 7.27±7.39 (m, 5H),
13C NMR d 11.98, 14.40, 65.68, 66.34, 107.67, 125.87, 127.61,
128.38, 141.97, 166.92, 169.76. Anal. Calcd for C13H15NO3: C,
66.94, H, 6.48, N, 6.00. Found: C, 66.80, H, 6.45, N, 5.93.
6. Falch, E.; Brehm, L.; Mikkelsen, I.; Johansen, T. N.;
Skjñrbñk, N.; Nielsen, B.; Stensbùl, T. B.; Ebert, B.;
Krogsgaard-Larsen, P. J. Med. Chem. 1998, 41, 2513±2523.
È
7. Brauner-Osborne, H.; Nielsen, B.; Krogsgaard-Larsen, P. Eur.
J. Pharmacol. 1998, 350, 311±316.
3.1.19. 4-Benzoyl-3-ethoxy-5-methylisoxazole (22). To a
solution of compound 4 (2.0 g, 7.9 mmol) in THF (40 mL),
cooled to 2308C, was dropwise added 2.0 M isopropyl-
magnesium bromide in THF (5.0 mL, 9.9 mmol). The reac-
tion mixture was heated to 08C and left for 1 h followed by
addition of benzoyl chloride (4 mL). The reaction was
heated to rt and left for 4 h followed by addition of a satu-
rated solution of NH4Cl in water (40 mL). The organic
phase was washed with water, dried (MgSO4), ®ltered and
concentrated in vacuo. CC (toluene, 1% AcOH) gave 22 as
white crystals (1.4 g, 77%). Recrystallization (hexane) gave
white crystals: mp 59±608C, 1H NMR d 1.28 (t, Jˆ7.1 Hz,
3H), 2.50 (s, 3H), 4.30 (q, Jˆ7.1 Hz, 2H), 7.46 (dd, Jˆ7.1,
7.1 Hz, 2H), 7.59 (dd, Jˆ7.1, 7.1 Hz, 1H), 7.79 (d, Jˆ
7.1 Hz, 2H), 13C NMR d 13.58, 14.18, 66.12, 107.91,
128.13, 129.38, 133.10, 137.76, 168.62, 175.99, 188.70.
Anal. Calcd for C13H13NO3: C, 67.52, H, 5.67, N, 6.06.
Found: C, 67.39, H, 5.67, N, 6.02.
È
8. Johansen, T. N.; Ebert, B.; Brauner-Osborne, H.; Didriksen,
M.; Christensen, I. T.; Sùby, K. K.; Madsen, U.; Krogsgaard-
Larsen, P.; Brehm, L. J. Med. Chem. 1998, 41, 930±939.
9. Jacobsen, N.; Kolind-Andersen, H.; Christensen, J. Can. J.
Chem. 1984, 62, 1940±1944.
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1831±1837.
11. Sùrensen, U. S.; Falch, E.; Krogsgaard-Larsen, P. J. Org.
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13. Mitchell, T. N. Synthesis 1992, 803±815.
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3.1.20. 3-Ethoxy-5-methyl-4-(4-methylphenyl)isoxazole
(23). To a solution of compound 4 (0.45 g, 1.8 mmol) in
THF (10 mL), cooled to 2308C, was dropwise added
1.5 M isopropylmagnesium bromide in THF (1.5 mL,
2.2 mmol). The reaction mixture was heated to 08C and
left for 1 h followed by addition of ZnCl2 (340 mg,
2.5 mmol) in THF (5 ml). The reaction was heated to rt
and left for an additional hour. 4-Iodotoluene (1.3 g,
6.0 mmol) and Pd(PPh3)2Cl2 (40 mg, 0.06 mmol) were
added and the reaction mixture was left overnight. A
saturated solution of NH4Cl in water (20 mL) was added,
and the organic phase was washed with water, dried
(MgSO4), ®ltrated, and concentrated in vacuo. CC (toluene,
1% AcOH) gave 23 as yellow crystals (310 mg, 80%).
Recrystallization (heptane) gave white crystals: mp: 61.5±
628C, 1H NMR d 1.43 (t, Jˆ7.2 Hz, 3H), 2.38 (s, 3H), 2.43
(s, 3H), 4.36 (q, Jˆ7.1 Hz, 2H), 7.23 (d, Jˆ8.0 Hz, 2H),
7.32 (d, Jˆ8.2 Hz, 2H), 13C NMR d 12.52, 14.54, 21.09,
65.55, 106.87, 126.17, 128.27, 129.37, 137.11, 165.79,
169.72. Anal. Calcd for C13H15NO2: C, 71.87, H, 6.96, N,
6.45. Found: C, 71.70, H, 6.99, N, 6.41.
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