Evaluation of protecting groups for 3-hydroxyisoxazoles - Short access to 3-alkoxyisoxazole-5-carbaldehydes and 3-hydroxyisoxazole-5-carbaldehyde, the putative toxic metabolite of muscimol

Article abstract of DOI:10.1002/(SICI)1099-0690(199803)1998:3<473::AID-EJOC473>3.0.CO;2-V

The regioselectivity of the 3-hydroxyisoxazole-5-ester 1 is studied with respect to O- versus N-alkylation. 3-O-Alkyl products 2 are highly favoured with benzyl, benzhydryl, and allyl bromide (≥ 91:9), in contrast to known uses of 5-alkyl-3-hydroxyisoxazoles or when methylation with diazomethane (or methyl iodide) is effected. Methoxymethylation leads to the N-substituted isoxazolinone 3e only. On reduction with DIBAH, the esters 2 afford 3-O-protected 3-hydroxyisoxazole-5-carbaldehydes 4 (75-98%). For removal of the benzyl protecting groups, three variations (HBr/HOAc, H₂/ Pd/BaSO₄, NBS/AIBN) were found useful with 5-ester, 5-formyl, and 5-hydroxymethyl derivatives. The free 3-hydroxy-5-carbaldehyde 9, the putative toxic metabolite of the GABA agonist muscimol, is prepared accordingly. The O-protected 3-hydroxyisoxazole-5-carbaldehydes 4 constitute versatile intermediates in various routes to analogues of CNS-active amino acids and can now be obtained in a highly efficient manner.

Full text of DOI:10.1002/(SICI)1099-0690(199803)1998:3<473::AID-EJOC473>3.0.CO;2-V

FULL PAPER
Evaluation of Protecting Groups for 3-Hydroxyisoxazoles ؊ Short Access to
3-Alkoxyisoxazole-5-carbaldehydes and 3-Hydroxyisoxazole-5-carbaldehyde,
the Putative Toxic Metabolite of MuscimolȠ[1]
Regine Riess, Michael Schön, Sabine Laschat, and Volker Jäger*
Institut für Organische Chemie der Universität Stuttgart,
Pfaffenwaldring 55, D-70569 Stuttgart, Germany
Fax: (internat.) ϩ 49(0)711/685-4321
E-mail: jager.ioc@po.uni-stuttgart.de
Received September 17, 1997
Keywords: 3-Hydroxyisoxazoles / Alkylation / Protecting groups / Muscimol / GABA analogues
The regioselectivity of the 3-hydroxyisoxazole-5-ester 1 is
studied with respect to O- versus N-alkylation. 3-O-Alkyl
benzyl protecting groups, three variations (HBr/HOAc, H2/
Pd/BaSO4, NBS/AIBN) were found useful with 5-ester, 5-for-
products 2 are highly favoured with benzyl, benzhydryl, and myl, and 5-hydroxymethyl derivatives. The free 3-hydroxy-
allyl bromide (Ն 91:9), in contrast to known uses of 5-alkyl- 5-carbaldehyde 9, the putative toxic metabolite of the GABA
3-hydroxyisoxazoles or when methylation with diazome- agonist muscimol, is prepared accordingly. The O-protected
thane (or methyl iodide) is effected. Methoxymethylation 3-hydroxyisoxazole-5-carbaldehydes 4 constitute versatile
leads to the N-substituted isoxazolinone 3e only. On reduc- intermediates in various routes to analogues of CNS-active
tion with DIBAH, the esters 2 afford 3-O-protected 3-hydro-
xyisoxazole-5-carbaldehydes 4 (75Ϫ98%). For removal of the
amino acids and can now be obtained in a highly efficient
manner.
Muscimol A[2] (5-aminomethyl-3-hydroxyisoxazole), the Figure 1. Examples of naturally occurring or synthetic 3-hydroxy-
isoxazoles of pharmaceutical interest
psycho-active, toxic constituent of the mushrooms Amanita
muscaria and A. pantherina, is known to be a potent agonist
of the GABAA receptor (GABA ϭ γ-aminobutyric acid).[3]
Since the discovery of its remarkable CNS activity, much
attention has been focussed on the synthesis of related 3-
hydroxyisoxazoles (Figure 1).[4Ϫ20] The most common ex-
amples are 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol
(THIP; B),[2][9a] a bicyclic and less toxic analogue of musci-
mol, and the glutamic acid analogues ibotenic acid
(C),[3b][14] and (S)-2-amino-3-(3-hydroxy-4-isoxazolyl)pro-
pionic acid [(S)-AMPA; D][2][3b][5b]. THIP (B) has been sub-
jected to clinical trials with epileptic patients, but no signifi-
cantly positive effects were detected.[8b] The above com-
pounds may be regarded as conformationally restricted bio-
isosteres[15] of neurotransmitters such as γ-aminobutyric
acid (GABA),[3a] glutamic acid, or N-methyl--aspartic
So far, O-protection has mostly been effected by meth-
acid (NMDA).[3b] Although the 3-hydroxyisoxazole moiety
ylation of 3-hydroxyisoxazole anions with methyl iodide or
thus represents an important group, only a few general ap-
diazomethane.[4][11][16][18][21] However, this gives rise to mix-
proaches for their synthesis are presently known.[16]
tures of the two regioisomeric O- and N-alkylated products
We now give a full account of the synthesis of O-pro- (vide infra), which have to be separated by chromatography.
tected 3-hydroxyisoxazole-5-carbaldehydes 4.[1d][1e] If ef- Rather limited studies exist concerning the dependence of
ficient deprotections were feasible, such intermediates might the O/N-regioisomer formation on the substitution pattern
serve as versatile building blocks for short syntheses of new of the 3-hydroxyisoxazole and on the type of re-
3-hydroxyisoxazoles, with the aldehyde function allowing agent.[11b][19a][21] For example, methylation of 3-hydroxy-
for various modifications of the side-chain in position 5. 4,5-dimethylisoxazole with methyl iodide/potassium car-
We chose the commercially available 3-hydroxyisoxazole-5- bonate led to the N-methylisoxazolidinone only, while a ra-
ester 1[17] as a starting and test material, in order to trans- tio of 58:42 of O/N-methyl derivatives was produced on re-
form it into various 5-carbaldehydes 4 after OH protection action with diazomethane.[11b][21] Similar results were found
and subsequent reduction of the intermediate esters 2 (see with 5-(diethoxymethyl)-3-hydroxyisoxazole.[19a] Notably,
Scheme 1).
benzylation here[19a] and with 3-hydroxy-5-methylisoxazole
Eur. J. Org. Chem. 1998, 473Ϫ479
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1434Ϫ193X/98/0303Ϫ0473 $ 17.50ϩ.50/0
473

R. Riess, M. Schön, S. Laschat, V. Jäger
FULL PAPER
Scheme 1. Preparation of protected 3-hydroxyisoxazole-5-esters 2 difference of only 1 kcal/mol in free activation enthalpies,
∆∆G϶298), this effect of the 5-methoxycarbonyl substituent
and -carbaldehydes 4
is of great practical significance.
The highest O/N-product ratio was obtained in the case
of the benzhydryl group (entry 3), a typical SN1-type alkyl-
ating agent. The allyl and benzyl reagents proved slightly
less regioselective (entries 2 and 4). However, the use of the
somewhat less effective benzyl group (entry 2) eventually
turned out to be preferable, since the benzhydryl group
showed a tendency to migrate in some of the subsequent
reactions studied.[1a] An example of a protecting group,
which could be introduced selectively at the nitrogen atom,
is the methoxymethyl moiety (entry 5); however, here the
DIBAH reduction to the respective aldehyde failed and in-
tractable mixtures were formed (vide infra).[1] On the other
hand, the 3-O-alkyl-hydroxyisoxazoles 2aϪd could readily
2, 3
R
a
b
c
d
e
be reduced to the corresponding aldehydes 4a؊d by means
of diisobutylaluminium hydride (DIBAH) (see Table 2).
With the free 3-hydroxyisoxazole ester 1, this had only led
to mixtures and low yields.[1c]
Me Bn
Bzh
c
All
d
MOM
4
a
b
R
Me Bn
Bzh
All
Table 2. DIBAH reduction of O-alkylated 3-hydroxyisoxazole-5-
esters 2
(tachigarene)[10a] led to mixtures with regioisomeric ratios
of 62:38 and 56:44, respectively, for O-/N-benzyl products.
Another disadvantage of using methoxy derivatives is that
rather harsh conditions are required for the final O-demeth-
ylation (e. g. reflux in 48% HBr[7a]). There are few examples
of the use of the benzyl (Bn),[10a][19] p-methoxybenzyl
(PMB),[8a] methoxymethyl (MOM),[5] phenylsulfonyl,[20] or
benzoyl[21] groups in this series.
We have examined the suitability of various protecting
groups for 3-hydroxyisoxazoles, in order to find out
whether they could selectively be introduced at the oxygen
atom and removed under mild reaction conditions. As
shown below, only 3-O-alkyl compounds (isoxazolol deriva-
tives) are subject to clean reduction of the 5-ester function
to the formyl group. The O/N-alkyl ratios observed when
the 3-hydroxyester 1 was submitted to several such trans-
formations are summarized in Table 1.
Entry
R
Starting material
Product
Yield [%]
1
2
3
4
Me
Bn
Bzh
All
2a
2b
2c
2d
4a
4b
4c
4d
93
98
90
75
The merits of the above two-step sequence to produce
3-O-protected isoxazole-5-carbaldehydes 4 are evident on
comparison with earlier approaches: For example, the alde-
hyde 4a had been obtained in 5 steps in 4% yield from 2-
(2-nitrovinyl)furan[2a][11b][18b][19b] or from 3,3-diethoxypro-
pyne in 5 steps in 21% yield,[19a] as a key intermediate in
syntheses of, inter alia, muscimol,[2a][18b] ibotenic
acid,[19a] and homoibotenic acid.[11b] With sodium tetrahy-
dridoborate[19c], clean reduction of the ester group to the
primary alcohol occurred in 2b to give 5 and in the isoxazo-
linone 3e to give 6 (eqs. 1, 2).
Table 1. Ratios of O-/N-alkyl products 2 and 3 from 3-hydroxy-
isoxazole 1
Entry
R
Reagent, Method
2/3[a]
Yield [%][b]
1
Me
Bn
CH2N2, A
73:27
94:6
57 (2a) 21 (3a)
2
PhCH2Br, B
Ph2CHBr, B
93 (2b)
5 (3b)
3
Bzh
All
> 95:5
94 (2c) Ϫ (3c)
4
H2CϭCHCH2Br, B 91:9
80 (2d)
8 (3d)
5
MOM (MeO)2CH2, C
Me
< 5:95
58:42
Ϫ (2e) 97 (3e)
57 (2a) 41 (3a)
6[21]
MeI
[a]
Ratios determined from the crude reaction product by 13C
[b]
NMR. Ϫ Yield of isolated, analytically pure products; reaction
conditions: A: Et2O, 0°C; B: K2CO3, acetone, reflux; C: P4O10,
CHCl3, room temp.
While the isomer ratio of methylation with diazomethane
With viable methods for protection of the OH function
(entry 1) is within the usual range, the O-benzyl, O-benzhy- of the isoxazole ester 1 and efficient reductions at hand,
dryl, and O-allyl products were formed with unexpectedly appropriate methods for deprotection were studied (see
high regioselectivity (entries 2Ϫ4). Although small in terms Table 3). Three variations were found to be successful for
of energy (a change from 73:27 to 94:6 corresponds to a the benzyl ethers: (i) Acid-catalyzed cleavage of the ester 2b
474
Eur. J. Org. Chem. 1998, 473Ϫ479

Short Access to 3-Alkoxyisoxazole-5-carbaldehydes and 3-Hydroxyisoxazole-5-carbaldehyde
FULL PAPER
with 33% HBr/HOAc at room temperature: This gave back
Finally, the free 3-hydroxyisoxazole-5-carbaldehyde (9)
the free hydroxyisoxazole ester 1 in good yield (entry 1), was prepared from the benzyloxy aldehyde 4b, using 33%
under conditions similar to those applied earlier for depro- HBr/HOAc, in 61% yield (eq. 5). This aldehyde had first
tection of 3-methoxyisoxazoles[4][11][16][18] or 3-benzyloxy- been prepared by Nakamura et al.[18a][19a] starting from 3,3-
isoxazoles.[19b] (ii) Catalytic hydrogenation (entry 2): Al- diethoxypropyne, in 50% yield over 5 steps. It is presumed
though sporadic examples using Pd on C are known in the to be the first major metabolite of muscimol and suppos-
literature,[9a] hydrogenolysis of the O-benzyl bond of iso- edly causes the pronounced toxicity of this compound.[2] It
xazolol derivatives proved troublesome at first. However, is further known, that muscimol is degraded rapidly in vivo,
the use of RosenmundЈs catalyst (Pd on BaSO4) in most probably by transamination catalyzed by GABA amino-
cases gave none of the acyclic by-products and the free transferase; while this should afford the aldehyde 9, actual
hydroxyisoxazole 1 was again isolated in good yield (entry metabolites of muscimol have not yet been identified[2] and
2). (iii) Alternatively, deprotection of the O-alkyl esters 2b the toxicity of 9 remains to be studied.
with NBS, according to Anson et al,[22] could also be
achieved in high yield (entry 3).
The protected aldehydes 4, notably the benzyl derivative
4b, have proven useful for syntheses of, inter alia, vinylene-
muscimol[1d][1e] and 3-hydroxyisoxazolyl-substituted β-lac-
tams,[23] to be detailed elsewhere.
Table 3. Deprotection of O- and N-benzyl-3-hydroxyisoxazole deri-
vatives[a]
As mentioned above, only the 3-alkoxyisoxazole-5-esters
underwent clean reduction to afford the appropriate alde-
hydes. In order to complement the above scheme, an ap-
proach towards N-alkylated isoxazolinone-5-carbaldehydes
was also sought: Indeed, oxidation of the alcohol 6 with
manganese dioxide[24] gave rise to the aldehyde 10 (eq. 6),
another potential intermediate in the synthesis of 3-
hydroxyisoxazoles of pharmacological interest.
Entry
Starting material Method
Product
Yield [%]
1
2
3
4
5
6
7
8
2b
2b
2b
3b
3b
4b
5
A
B
C
B
C
B
B
A
1
1
1
7
1
8
8
9
88
84
98
91
96
98
98
61
4b
[a]
Method A: 33% HBr/HOAc, room temp., 1 d; Method B: H2,
Pd/BaSO4, MeOH; Method C: NBS, AIBN, CCl4, ∆T, then H2O.
With the isoxazolinone ester 3b, catalytic hydrogenation
(method B) led to ring cleavage and gave the acetoacetam-
ide 7; however, deprotection with NBS occurred smoothly
(entries 4, 5 and eq. 3).
A further objective of this work dealt with the prep-
In conclusion, we have devised a short route towards pro-
aration of the 3-hydroxyisoxazole-5-carbaldehyde 9. DI- tected 3-hydroxyisoxazole-5-carbaldehydes 4 and 10, versa-
BAH reduction of the ester 1 had failed (vide supra). Cata- tile key intermediates in the synthesis of known or new 3-
lytic hydrogenation of the supposedly suitable precursor 4b, hydroxyisoxazoles of pharmacological interest. These alde-
however, caused removal of the O-benzyl group along with hydes are readily available in gram quantities in two steps
reduction of the aldehyde function. Thus, the free 5- (up to 91% overall yield), starting from the commercially
hydroxymethylisoxazole 8 was obtained in nearly quantitat- available isoxazole ester 1, by regioselective O-alkylation
ive yield, similar to the result with the 3-benzyloxy alcohol and subsequent DIBAH reduction. Further studies based
5 (entries 6, 7 and eq. 4).
on this work are in progress.
Eur. J. Org. Chem. 1998, 473Ϫ479
475

R. Riess, M. Schön, S. Laschat, V. Jäger
FULL PAPER
We are grateful to the Fonds der Chemischen Industrie for a doc-
toral fellowship (to R. R.) and general support, to the Hoechst AG
ethyl acetate, to give 5.32 g of a yellowish solid after the removal
of volatiles, containing 2b/3b ϭ 91:9 (GC analysis). Separation of
(Dr. U. Gebert, Dr. H. Mildenberger) for providing some biological the two regioisomers by flash chromatography on silica gel (column
tests (no significant activity detected), to the Bayer AG for the do-
nation of chemicals, and to Ms. Sabine Ebeling for experimental
help.
25 cm ϫ 3 cm, ethyl acetate/petroleum ether, 6:4) afforded 5.25 g
(93%) of O-benzylisoxazole 2b and 310 mg (5%) of N-benzyl de-
rivative 3b, both as colourless crystals, in analytically pure form. Ϫ
2b: M.p. 43°C. Ϫ IR (KBr): ν˜ ϭ 1735 cmϪ1 (CϭO), 1500, 1460,
1360. Ϫ 1H NMR (CDCl3, 200 MHz): δ ϭ 3.90 (s, 3 H, CH3), 5.29
(s, 2 H, OCH2), 6.55 (s, 1 H, 4-H); 7.25Ϫ7.40 (m, 5 H, C6H5). Ϫ
13C NMR (CDCl3, 50.3 MHz): δ ϭ 52.6 (q, CH3), 72.0 (t, OCH2),
100.7 (d, C-4); 128.2, 128.3, 128.5 (3 d, o-, m-, p-C6H5), 135.2 (s, i-
Experimental Section
Solvents and reagents were purified and dried according to
standard procedures. Ϫ TLC analyses were done on Si60 F254
-
coated aluminium sheets (E. Merck) using ethyl acetate/petroleum
ether (b.p. 30Ϫ75°C) mixtures; detection by UV at 254 nm or phos-
phomolybdic acid (10% in EtOH). Silica gel 0.040Ϫ0.063 mm (E.
Merck) was used for flash chromatography, with eluents as above.
Ϫ Melting points were determined with a Tottoli apparatus, Fisher
Jones 4017 or a heat bar (Kofler system) and are uncorrected. Ϫ
B.p. refer to bath temperatures of kugelrohr distillations. Ϫ IR
spectra were recorded with a Perkin-Elmer 4120 or Bruker IFS 28
spectrometer. Ϫ NMR spectra were obtained with Bruker AC 200
and 250 spectrometers (1H: 200.1, 250.1 MHz; 13C: 50.3, 62.9
MHz), with TMS as internal standard; evaluation of 1H-NMR
spectra according to first-order interpretation; multiplicity of 13C-
NMR signals from DEPT spectra. Ϫ Mass spectra were recorded
with a Finnigan MAT 95 spectrometer.
C6H5), 156.9 (s, C-5), 160.3 (COOMe), 171.8 (s, C-3).
Ϫ
C12H11NO4 (233.2): calcd. C 61.80, H 4.71, N 6.01; found C 61.90,
H 4.68, N 5.90. Ϫ 3b: M.p. 99°C. Ϫ IR (KBr): ν˜ ϭ 1725 cmϪ1
(CϭO), 1670 (NCϭO), 1255. Ϫ 1H NMR (CDCl3, 200 MHz): δ ϭ
3.90 (s, 3 H, CH3), 5.13 (s, 2 H, NCH2), 6.40 (s, 1 H, 4-H), 7.34 (s,
5 H, C6H5). Ϫ 13C NMR (CDCl3, 50.3 MHz): δ ϭ 49.5 (q, CH3),
53.0 (t, NCH2), 106.2 (d, C-4); 128.0, 128.3, 128.6 (3 d, o-, m-, p-
C6H5), 134.0 (s, i-C6H5), 156.5 (s, C-5), 160.0 (COOMe), 164.4 (s,
C-3). Ϫ C12H11NO4 (233.2): calcd. C 61.80, H 4.71, N 6.01; found
C 61.88, H 4.83, N 5.79.
Methyl 3-(Benzhydryloxy)isoxazoline-5-carboxylate (2c): A sus-
pension of 0.78 g (5.5 mmol) of ester 1 and 1.52 g (11.0 mmol) of
K2CO3 in 15 ml of acetone was heated to 70°C for 1 h. After
addition of 1.37 g (7.0 mmol) benzhydryl bromide over a period of
15 min, stirring was continued for 3 h at 70°C and for 12 h at room
temp. The mixture was filtered and concentrated in vacuo to afford
1.98 g of a pale yellow oil (2c/3c > 95:5). The residue was purified
by filtration through silica gel (column 15 cm ϫ 3 cm) with petro-
leum ether/ethyl acetate (95:5; to remove excess benzhydryl bro-
mide), then petroleum ether/ethyl acetate (80:20), which gave, after
removal of the solvents, 1.60 g (94%) of analytically pure O-
benzhydryl compound 2c as colourless needles, m.p. 159°C. Ϫ IR
(KBr): ν˜ ϭ 1730 cmϪ1 (CϭO), 1655, 1265. Ϫ 1H NMR (CDCl3,
250 MHz): δ ϭ 3.82 (s, 3 H, CH3), 6.34 (s, 1 H, OCHPh2), 6.80 (s,
1 H, 4-H), 7.16Ϫ7.32 (m, 5 H, C6H5). Ϫ 13C NMR (CDCl3, 62.9
MHz): δ ϭ 53.6 (q, CH3), 63.4 (d, OCHPh2), 106.3 (d, C-4); 128.3,
128.4, 128.7 (3 d, o-, m-, p-C6H5); 137.0 (s, i-C6H5), 156.7 (s, C-5),
157.5 (COOMe), 166.0 (s, C-3). Ϫ C18H15NO4 (309.3): calcd. C
69.90, H 4.89, N 4.53; found C 70.11, H 4.87, N 4.47.
Introduction of Protecting Groups
Methyl 3-(Methoxy)isoxazole-5-carboxylate (2a) and Methyl 2-
Methyl-3-oxoisoxazoline-5-carboxylate (3a): At Ϫ5°C, a suspension
of 5.20 g (36.4 mmol) of the ester 1[17] in 40 ml of diethyl ether
was treated with 130 ml of a ca. 0.4  ethereal diazomethane solu-
tion. The reaction mixture was stirred for 18 h at Ϫ5°C and filtered
to remove starting material (270 mg, 5%). Excess diazomethane
was destroyed by addition of acetic acid (10 ml). The solution was
washed with sat. aqueous NaHCO3 (3 ϫ 30 ml), dried with MgSO4,
and concentrated to afford 4.5 g (79%) of a yellow solid. The two
regioisomers 2a, 3a (ratio 73:27 by 1H NMR) were separated by
flash chromatography (ethyl acetate/petroleum ether, 1:1) to yield
3.25 g (57%) of analytically pure O-methyl ester 2a and 1.20 g
(21%) of analytically pure N-methyl ester 3a, both as colourless
crystals. Ϫ 2a: M.p. 71Ϫ72°C (ref.[21][25] 72Ϫ73°C). Ϫ IR (KBr):
ν˜ ϭ 1745 cmϪ1 (CϭO), 1605, 1410, 1310, 800. Ϫ 1H NMR (CDCl3,
200 MHz): δ ϭ 3.96 (s, 3 H, COOCH3), 4.03 (s, 3 H, OCH3),
6.55 (s, 1 H, 4-H). Ϫ 13C NMR (CDCl3, 50.3 MHz): δ ϭ 52.7 (q,
COOCH3), 57.4 (q, OCH3), 100.6 (d, C-4), 157.0 (s, C-5), 160.4 (s,
COOCH3), 172.0 (s, C-3). Ϫ C6H7NO4 (157.0): calcd. C 45.86, H
4.46, N 8.92; found C 46.04, H 4.56, N 8.81. Ϫ 3a: M.p.
123Ϫ124°C (ref.[21] 120Ϫ121°C). Ϫ IR (KBr): ν˜ ϭ 1725 cmϪ1
Methyl 3-(Allyloxy)isoxazole-5-carboxylate (2d) and Methyl 2-
Allyl-3-oxoisoxazoline-5-carboxylate (3d): A suspension of 286 mg
(2.00 mmol) of the ester 1 and 552 mg (4.00 mmol) of K2CO3 in
10 ml of acetone was heated to 60Ϫ70°C for 1 h. After addition
of 363 mg (24.0 mmol) of allyl bromide over a period of 20 min,
stirring was continued for 3.5 h at 60Ϫ70°C (TLC control). The
mixture was filtered through silica gel and concentrated in vacuo
to afford 330 mg of a yellow oil (2d/3d ϭ 91:9 from 1H NMR).
Separation of the two regioisomers by MPLC on silica gel (ethyl
acetate/petroleum ether, 6:4) yielded 213 mg (80%) of analytically
pure O-allyl ester 2d as a colourless oil and 21 mg (8%) of analyti-
cally pure N-allyl ester 3d as colourless crystals, m.p. 47°C. Ϫ On
a larger scale (16 mmol of 1), practically identical results were ob-
tained. The pure regioisomers did not rearrange on heating to
1
(CϭO), 1665 (NCϭO), 1380, 1305, 910. Ϫ H NMR (CDCl3, 200
MHz): δ ϭ 3.60 (s, 3 H, COOCH3), 3.95 (s, 3 H, OCH3), 6.40 (s,
1 H, 4-H). Ϫ 13C NMR (CDCl3, 50.3 MHz): δ ϭ 32.4 (q, CO-
OCH3), 53.1 (q, OCH3), 106.1 (d, C-4), 156.4 (s, C-5), 156.6 (s, C-
3), 164.5 (s, COOCH3). Ϫ C6H7NO4 (157.0): calcd. C 45.86, H
4.46, N 8.92; found C 45.40, H 4.42, N 8.63.
Methyl 3-(Benzyloxy)isoxazole-5-carboxylate (2b) and Methyl 2-
Benzyl-3-oxoisoxazoline-5-carboxylate (3b): A suspension of 3.50 g 140°C in xylene for 12 h. Ϫ 2d: IR (KBr): ν˜ ϭ 1735 cmϪ1 (CϭO),
(24.5 mmol) of ester 1 and 6.9 g (50 mmol) of K2CO3 in 60 ml of 1600, 1305, 1285, 1220, 1105, 995. Ϫ 1H NMR (CDCl3, 250 MHz):
3
4
acetone was heated to 70°C for 1 h. After addition of 6.3 g (37 δ ϭ 3.28 (s, 3 H, COOCH3), 4.54 (dt, J1Ј,2Ј ϭ 5.7, J1Ј,3ЈE
ϭ
mmol) of benzyl bromide over a period of 30 min, stirring was 4J1Ј,3ЈZ ϭ 1.3 Hz, 2 H, 1Ј-H), 5.01 (dm, J2Ј,3EЈ ϭ 10.5 Hz, 1 H, 3Ј-
3
3
3
continued for 3 h at 70°C and for an additional 18 h at room temp.
The mixture was filtered and concentrated in vacuo to afford 8.0 g 5.6, J2Ј,3EЈ ϭ 10.5, J2Ј,3ZЈ ϭ 17.2 Hz, 1 H, 2Ј-H), 6.34 (s, 1 H, 4-
of a pale-yellow oil (2b, 3b and some benzyl bromide). The mixture
H). Ϫ 13C NMR (CDCl3, 62.9 MHz): δ ϭ 52.7 (q, OCH3), 70.8 (t,
was filtered through silica gel (column 10 cm ϫ 3 cm) with petro- C-1Ј), 100.7 (d, C-4), 119.2 (t, C-3Ј), 131.5 (d, C-2Ј), 157.0 (s, C-
HE), 5.15 (dm, J2Ј,3ZЈ ϭ 17.2 Hz, 1 H, 3Ј-HZ), 5.78 (ddt, J1Ј,2Ј ϭ
3
3
leum ether/ethyl acetate (95:5) and the products were eluted with
5), 160.1 (s, COOMe), 171.1 (s, C-3). Ϫ C8H9NO4 (183.2): calcd.
476
Eur. J. Org. Chem. 1998, 473Ϫ479

Short Access to 3-Alkoxyisoxazole-5-carbaldehydes and 3-Hydroxyisoxazole-5-carbaldehyde
FULL PAPER
C 52.51, H 4.91, N 7.64; found C 52.77, H 4.78, N 7.54. Ϫ 3d: IR
1 H, CHO). Ϫ 13C NMR (CDCl3, 50.3 MHz): δ ϭ 72.2 (t,
(KBr): ν˜ ϭ 1735 cmϪ1 (CϭO), 1660 (NCϭO), 1635, 1240. Ϫ 1H OCH2Ph), 100.0 (d, C-4); 128.0, 128.2, 128.6 (3 d, o-, m-, p-C6H5);
NMR (C6D6, 200 MHz): δ ϭ 2.92 (s, 3 H, COOCH3), 3.90 (dt, 135.0 (s, i-C6H5), 165.8 (s, C-5), 171.4 (s, C-3), 178.4 (d, CHO). Ϫ
4
3J1Ј,2Ј ϭ 5.8, J1Ј,3ЈE
ϭ
4J1Ј,3ЈZ ϭ 1.3 Hz, 2 H, 1Ј-H), 4.69 (dm, C11H9NO3 (203.2): calcd. C 65.02, H 4.46, N 6.89; found C 64.78,
3J2Ј,3ЈE ϭ 10.1 Hz, 1 H, 3Ј-HE), 4.74 (dm, J2Ј,3ЈZ ϭ 17.1 Hz, 1 H,
H 4.40, N 6.73.
3
3
3
3
3Ј-HZ), 5.28 (ddt, J1Ј,2Ј ϭ 5.8, J2Ј,3E ϭ 10.1, J2Ј,3Z ϭ 17.1 Hz, 1
H, 2Ј-H), 5.87 (s, 1 H, 4-H). Ϫ 13C NMR (C6D6, 50.3 MHz): δ ϭ
48.3 (q, 1Ј-H), 52.1 (q, COOCH3), 106.2 (d, C-4), 119.2 (t, C-3Ј),
128.3 (d, C-2Ј), 156.7 (s, C-5), 161.2 (s, COOMe), 168.5 (s, C-3). Ϫ
C8H9NO4 (183.2): calcd. C 52.51, H 4.91, N 7.64; found C 52.83,
H 4.74, N 7.71.
3-(Benzhydryloxy)isoxazole-5-carbaldehyde (4c): According to
the Typical Procedure given for 4a, 1.01 g (3.30 mmol) of ester 2c,
4.7 ml (4.7 mmol) of DIBAH (1  solution in hexane) in 20 ml of
anhydrous CH2Cl2 were allowed to react for 3 h at Ϫ78°C. Hy-
drolysis with 4.5 ml of MeOH and 10 ml of 1  HCl was followed
by extraction with 3 ϫ 10 ml CH2Cl2. Evaporation of the solvents
in vacuo afforded 830 mg (90%) of analytically pure aldehyde 4c,
colourless crystals, m.p. 84Ϫ85°C. Ϫ IR (CDCl3): ν˜ ϭ 1715 cmϪ1
(CϭO), 1490, 1455, 1035. Ϫ 1H NMR (CDCl3, 250 MHz): δ ϭ
6.62 (s, 1 H, 4-H), 6.76 (s, 1 H, CHPh2), 7.2Ϫ7.6 (m, 10 H, C6H5),
9.75 (s, 1 H, CHO). Ϫ 13C NMR (CDCl3, 62.9 MHz): δ ϭ 83.5 (d,
OCPh2), 100.1 (d, C-4); 126.5, 128.4, 128.6 (3 d, o-, m-, p-C6H5);
139.3 (s, i-C6H5), 165.8 (s, C-5), 170.8 (s, C-3), 178.6 (d, CHO). Ϫ
C17H13NO3 (279.3): calcd. C 73.11, H 4.69, N 5.02; found C 73.14,
H 4.80, N 4.64.
Methyl 2-(Methoxymethyl)3-oxoisoxazoline-5-carboxylate (3e):
A solution of 143 mg (1.00 mmol) of the ester 1 and 3.8 g (50
mmol) of 2,2-dimethoxypropane in 5 ml of CHCl3 was treated with
3.0 g (10 mmol) of P4O10, as described for the case of aliphatic
alcohols.[26] The resulting mixture was stirred for 22 h at room
temp., poured onto 20 ml of saturated aqueous Na2CO3, separated,
and cautiously extracted with CHCl3 (2 ϫ 20 ml). The combined
organic layers were washed with 30 ml of saturated aqueous NaCl,
dried with Na2SO4, and concentrated in vacuo to afford 248 mg of
a pale-yellow oil. Filtration through silica gel (methyl tert-butyl
ether/petroleum ether, 8:2) and subsequent kugelrohr distillation
(0.1 mbar, 120Ϫ140°C) afforded 148 mg (79%) of analytically pure
3e as a colourless oil. Ϫ IR (CCl4): ν˜ ϭ 1745 cmϪ1 (CϭO), 1697
3-Allyloxyisoxazole-5-carbaldehyde (4d): According to the Typi-
cal Procedure given for 4a, 2.2 g (12.0 mmol) of ester 2d, 15 ml
(15.0 mmol) of DIBAH (1  solution in hexane) in 30 ml of anhy-
drous CH2Cl2 were allowed to react for 75 min at Ϫ78°C. Hydroly-
sis with 1.5 ml of saturated aqueous NH4Cl and 3 ml of 2  HCl,
extraction with 5 ϫ 30 ml CH2Cl2, and Kugelrohr distillation
(120Ϫ140°C, 0.01 mbar) afforded 1.37 g (75%) of analytically pure
aldehyde 4d as a colourless oil. Ϫ IR (CDCl3): ν˜ ϭ 1700 cmϪ1 (Cϭ
1
(CϭO), 1247, 1230, 1105, 1045. Ϫ H NMR (CDCl3, 200 MHz):
δ ϭ 3.43 (s, 3 H, OCH3), 3.98 (s, 1 H, COOCH3), 5.25 (s, 2 H,
NCH2), 6.41 (1 H, 4-H). Ϫ 13C NMR (CDCl3, 50.3 MHz): δ ϭ
53.1 (q, COOCH3), 57.2 (q, OCH3), 74.9 (t, NCH2), 105.5 (d, C-
4), 156.5 (s, C-5), 157.8 (s, C-3), 165.0 (s, COOCH3). Ϫ C7H9NO5
(187.0): calcd. C 44.92, H 4.81, N 7.49; found C 44.83, H 4.80,
N 7.43.
O), 1590, 1495. Ϫ 1H NMR (CDCl3, 200 MHz): δ ϭ 4.81 (dt,
4
3J1Ј,2Ј ϭ 5.7, J1Ј,3ЈE
ϭ
4J1Ј,3ЈZ ϭ 1.5 Hz, 2 H, 1Ј-H), 5.35 (dt,
3J1Ј,3ЈE ϭ J3ЈE,3ЈZ ϭ 1.5, J2Ј,3ЈE ϭ 10.4 Hz, 1 H, 3Ј-HE), 5.45 (dt,
3
3
3J1Ј,3ЈZ ϭ 3J3ЈE,3ЈZ ϭ 1.5, 3J2Ј,3ЈZ ϭ 17.2 Hz, 1 H, 3Ј-HZ), 6.07 (ddt,
Reductions
3
3
3J1Ј,2Ј ϭ 5.7, J2Ј,3ЈE ϭ 10.4, J2Ј,3ЈZ ϭ 17.2 Hz, 1 H, 2Ј-H), 6.66 (s,
1 H, 4-H), 9.84 (s, 1 H, CHO). Ϫ 13C NMR (CDCl3, 50.3 MHz):
δ ϭ 70.2 (t, C-1Ј), 100.0 (d, C-4), 119.1 (t, C-3Ј), 131.2 (d, C-2Ј),
165.6 (s, C-5), 171.1 (s, C-3), 178.5 (d, CHO). Ϫ C7H7NO3 (153.1):
calcd. C 54.90, H 4.61, N 9.14; found C 54.86, H 4.87, N 9.13.
3-Methoxyisoxazole-5-carbaldehyde (4a). Ϫ Typical Procedure: A
25-ml flask, purged with N2, was charged with a solution of 850
mg (5.40 mmol) of 2a in 10 ml of anhydrous CH2Cl2. At Ϫ78°C,
6.5 ml (6.5 mmol) of DIBAH (1  solution in hexane) was added
dropwise by means of a syringe. Stirring was continued for 1 h at
Ϫ78°C. After hydrolysis with 1 ml of saturated aqueous NH4Cl
and 5 ml of 2  HCl, the two layers were separated and the aqueous
solutes was extracted with CH2Cl2 (5 ϫ 5 ml). The combined or-
ganic layers were dried with MgSO4 and concentrated in vacuo to
afford 746 mg of a pale-yellow oil. The crude product was purified
by kugelrohr distillation (115°C, 20 mbar; ref.[19a] b.p. 100Ϫ105°C,
19 Torr) to yield 635 mg (93%) of analytically pure aldehyde 4a as
a colourless oil. Ϫ IR (CCl4): ν˜ ϭ 1710 cmϪ1 (CϭO), 1415, 1380,
1100, 1030. Ϫ 1H NMR (CDCl3, 200 MHz): δ ϭ 4.04 (s, 3 H,
OCH3), 6.67 (s, 1 H, 4-H), 9.84 (s, 1 H, CHO). Ϫ 13C NMR
(CDCl3, 50.3 MHz): δ ϭ 57.8 (q, OCH3), 100.4 (d, C-4), 166.0 (s,
C-5), 172.4 (s, C-3), 178.9 (d, CHO). Ϫ C5H5NO (127.0): calcd. C
47.24, H 3.94, N 11.02; found C 47.02, H 4.03, N 11.17.
3-Benzyloxy-5-(hydroxymethyl)isoxazole (5): At 0°C 35 mg
(0.91 mmol) of sodium tetrahydridoborate was added to a solution
of 163 mg (0.70 mmol) of ester 2b in 5 ml of MeOH. The mixture
was stirred for 22 h, hydrolyzed with 10 ml of MeOH and 20 ml
of 1  HCl and extracted with CH2Cl2 (3 ϫ 20 ml). The combined
organic layers were dried with Na2SO4 and concentrated in vacuo.
Filtration through silica gel (column 4 cm ϫ 3 cm, ethyl acetate/
petroleum ether, 3:7) and subsequent kugelrohr distillation (120°C,
0.001 mbar) yielded 124 mg (87%) of analytically pure alcohol 5
as a colourless oil. Ϫ IR (CDCl3): ν˜ ϭ 1506 cmϪ1, 1457, 1365 (s),
818, 784, 651 (s) Ϫ 1H NMR (CDCl3, 250 MHz): δ ϭ 4.62 (s, 2
H, 5-CH2OH), 5.23 (s, 2 H, OCH2Ph), 5.89 (s, 1 H, 4-H);
7.31Ϫ7.53 (m, 5 H, C6H5). Ϫ 13C NMR (CDCl3, 62.9 MHz): δ ϭ
56.8 (t, CH2OH), 71.6 (t, OCH2Ph), 93.5 (d, C-4), 128.2, 128.5,
128.6 (3 d, o-, m-, p-C6H5), 135.6 (s, i-C6H5); 171.6, 172.3 (2 s, C-
3, C-5). Ϫ C11H11NO3 (205.2): calcd. C 64.38, H 5.40, N 6.83; C
64.04, H 5.56, N 6.78.
3-(Benzyloxy)isoxazole-5-carbaldehyde (4b): According to the
Typical Procedure given for 4a; 933 mg (4.0 mmol) of ester 2b, 4.8
ml (4.8 mmol) of DIBAH (1  solution in hexane) in 15 ml of
anhydrous CH2Cl2 were allowed to react for 1 h at Ϫ78°C. Hy-
drolysis with 0.5 ml of saturated aqueous NH4Cl and 2 ml of 2 
5-Hydroxymethyl-2-(methoxymethyl)isoxazoline-3-one (6): At
HCl was followed by extraction with 5 ϫ 10 ml CH2Cl2. Kugelrohr 0°C, 526 mg (13.9 mmol) of sodium tetrahydridoborate was added
distillation (120Ϫ140°C, 0.05 mbar) afforded 780 mg (98%) of ana- to a solution of 260 mg (1.39 mmol) of ester 3e in 10 ml of MeOH,
lytically pure aldehyde 4b as a colourless oil that crystallized on
and the reaction mixture was stirred at room temp. for 18 h. After
standing (ref.[19a]: b.p. 114Ϫ116°C/1 Torr, m.p. 42.5Ϫ43.5°C). Ϫ hydrolysis with 2 ml of 2  H2SO4, 5 g of strongly acidic ion ex-
IR (CCl4): ν˜ ϭ 1730 cmϪ1 (CϭO), 1695, 1590, 1495, 1440, 1355,
change resin (Lewatit S 100 G1) was added. The mixture was fil-
1280, 1030, 745, 695. Ϫ 1H NMR (CDCl3, 200 MHz): δ ϭ 5.30 (s, tered using 100 ml of methanol, then 5 g of weakly basic ion ex-
2 H, OCH2), 6.57 (s, 1 H, 4-H), 7.24Ϫ7.42 (m, 5 H, C6H5), 9.74 (s, change resin (Lewatit MP 62) was added. After filtration and rins-
Eur. J. Org. Chem. 1998, 473Ϫ479
477

R. Riess, M. Schön, S. Laschat, V. Jäger
FULL PAPER
ing with 100 ml of methanol, the filtrate was concentrated in vacuo C12H13NO4 (235.2): calcd. C 61.27, H 5.57, H 5.95; found C 60.94,
(45°C, 0.1 mbar) to afford 237 mg of a pale-yellow oil. Purification H 5.55, N 5.84.
of this material by filtration through silica gel (20 g, column 8 cm
Methyl 3-Hydroxyisoxazole-5-carboxylate (1) from N-Debenzyl-
ϫ 3 cm, 400 ml of ethyl acetate) yielded 183 mg (83%) of analyti-
ation of Isoxazolinone 3b with NBS: According to Method C, a
cally pure alcohol 6 as a colourless oil. Ϫ IR (CDCl3): ν˜ ϭ 1679
solution of 83 mg (0.36 mmol) of N-benzylisoxazolinone 3b, 69 mg
(0.39 mmol) of NBS, and 5 mg (0.3 µmol) of AIBN in 5 ml of CCl4
was heated under reflux for 2 h and worked up as described above.
The crude product (110 mg, yellow oil) was purified by flash chro-
matography (silica gel, 20 g, column 8 cm ϫ 3 cm, ethyl acetate/
petroleum ether, 6:4) to give 48 mg (96%) of pure hydroxyisoxazole
1 (vide supra) as colourless crystals, m.p. 164Ϫ165°C (ref.[17]
165°C).
1
cmϪ1 (NCϭO), 1378, 1097, 922, 727 (s). Ϫ H NMR (CDCl3, 250
MHz): δ ϭ 3.34 (s, 3 H, OCH3), 3.88 (br., 1 H, OH), 4.47 (d, J ϭ
5.0 Hz, 2 H, 5-CH2OH), 5.08 (s, 2 H, NCH2O), 5.69 (s, 1 H, 4-H).
Ϫ
13C NMR (CDCl3, 62.9 MHz): δ ϭ 56.7 (q, OCH3), 57.2 (t,
CH2OH), 75.2 (t, NCH2O), 97.5 (d, C-4), 167.9 (s, C-3), 173.6 (s,
C-5). Ϫ C6H9NO4 (159.1): calcd. C 45.28, H 5.70, N 8.80; found
C 44.96, H 5.64, N 8.58.
Deprotection
3-Hydroxy-5-(hydroxymethyl)isoxazole (8) by Hydrogenation of
the 3-O-Benzyloxyaldehyde 4b: According to Method B, 100 mg
(0.49 mmol) of aldehyde 4b, 30 mg Pd/BaSO4, 10 ml of MeOH.
Yield 55 mg (98%) of analytically pure hydroxyisoxazole 8 as
colourless crystals, m.p. 78Ϫ79°C [8 had been obtained in a 7-step
sequence[27] as a yellow, impure syrup, with 1H-NMR data (in
Methyl 3-Hydroxyisoxazole-5-carboxylate (1) from 3-O-Benzyl-
isoxazole 2b. Ϫ Method A (HBr/acetic acid): A solution of 221 mg
(0.95 mmol) of the ester 2b in 5 ml of 33% HBr in glacial acetic
acid was stirred for 1 d at room temp. After evaporation of the
solvents (40°C, 0.1 mbar), the remainder was dried in a desiccator
(KOH) and recrystallized from CHCl3 to afford 120 mg (88%) of
the analytically pure ester 1 as colourless crystals, m.p. 164Ϫ165°C
(ref.[17] 165°C), with spectroscopic data identical to those re-
ported.[17] Ϫ C5H5NO4 (143.1): calcd. C 41.97, H 3.52, N 9.79;
found C 41.98, H 3.39, N 9.76.
D O) in accord with data given below]. Ϫ IR (KBr): ν ϭ
˜
2
3600Ϫ2600 cmϪ1, 1620, 1520, 1330, 1055. Ϫ 1H NMR (CD3OD,
250 MHz): δ ϭ 4.56 (s, 2 H, CH2OH), 5.93 (s, 1 H, 4-H). Ϫ 13C
NMR (CD3OD, 62.9 MHz): δ ϭ 58.4 (t, CH2OH), 95.8 (d, C-4),
173.7 (s, C-5), 176.2 (s, C-3). Ϫ MS (FAB pos, NBA); m/z (%): 116
(100) [Mϩ ϩ H], 55 (20) [C2H2NOϩ ϩ H]. Ϫ C4H5NO3 (115.1):
calcd. C 41.75, H 4.38, N 12.17; found C 41.48, H 4.36, N 11.79.
Method B (Hydrogenation with Pd/BaSO4). Ϫ Typical Pro-
cedure: A suspension of 55 mg Pd/BaSO4 (5%) in 5 ml of MeOH
was stirred under H2 (1 bar) in a Schlenk tube until hydrogen con-
sumption had stopped. A solution of 62 mg (0.25 mmol) of the
ester 2b was added and the reaction mixture was again stirred until
hydrogen uptake had stopped. Solids were removed by means of a
centrifuge, washed with methanol (3 ϫ 10 ml), and the combined
solutions were concentrated in vacuo. Recrystallization of the resi-
due from CHCl3 afforded 32 mg (84%) of spectroscopically and
analytically pure ester 1 as colourless crystals, m.p. 164Ϫ165°C
(ref.[17] 165°C).
3-Hydroxy-5-hydroxymethylisoxazole (8) by Hydrogenation of the
3-O-Benzyloxyalcohol 5: According to Method B, 210 mg (1.02
mmol) of alcohol 5, 90 mg Pd/BaSO4 and 15 ml of MeOH. Yield
112 mg (98%) of analytically pure hydroxyisoxazole 8 as colourless
crystals, m.p. 78Ϫ79°C; data as above.
3-Hydroxyisoxazole-5-carbaldehyde (9) by Cleavage of the Benzyl-
oxy Compound 4b with HBr: According to Method A, a solution
of 203 mg (1.00 mmol) of the aldehyde 4b in 3 ml of 33% HBr in
glacial acetic acid was stirred for 24 h at room temp. (TLC control).
After evaporation of the solvents in vacuo, the viscous, yellow resi-
due was dried in a desiccator (KOH) and recrystallized from ben-
zene to afford 70 mg (61%) of analytically pure aldehyde 9 as
colourless crystals, m.p. 141°C (ref.[18a][19a] 141Ϫ142°C). Ϫ IR
Method C (NBS, AIBN): According to the procedure of Anson
et al.[22], a solution of 106 mg (0.455 mmol) of the 3-O-benzyliso-
xazole 2b, 88 mg (0.49 mmol) of NBS and 5 mg (0.3 µmol) of
AIBN in 7 ml of CCl4 was heated at reflux for 2 h. After evapor-
ation of the solvents in vacuo, the residue was dissolved in 20 ml
of ethyl acetate and washed with 10 ml of water. The aqueous layer
was extracted with ethyl acetate (3 ϫ 15 ml) and the combined
organic layers were dried with Na2SO4. After evaporation of the
solvents in vacuo the crude product (162 mg of a yellow oil) was
purified by flash chromatography (silica gel, 25 g, column 10 cm
ϫ 3 cm, ethyl acetate/petroleum ether, 7:3) to yield 64 mg (98%) of
the pure (vide supra) hydroxyisoxazole 1 as colourless crystals, m.p.
164Ϫ165°C (ref.[17] 165°C).
(KBr): ν ϭ 3280Ϫ2840 cmϪ1 (OH), 1710 (CϭO), 1495. Ϫ 1H NMR
˜
([D6]DMSO, 200 MHz): δ ϭ 6.85 (s, 1 H, 4-H), 9.74 (1 H, CHO).
Ϫ
13C NMR ([D6]DMSO, 62.9 MHz): δ ϭ 100.4 (d, C-4), 166.0 (s,
C-5), 171.8 (s, C-3), 178.5 (d, CHO). Ϫ C4H3NO3 (114.1): calcd.
C 42.49, H 2.67, N 12.39; found C 42.62, H 2.78, N 12.04.
2-(Methoxymethyl)-3-oxoisoxazoline-5-carbaldehyde
(10):
Manganese dioxide (3.18 g) was added to a solution of 318 mg
(2.00 mmol) of the alcohol 6 in 2 ml of CH2Cl2. The reaction mix-
ture was stirred for 18 h, filtered through Celite, and concentrated
in vacuo. Purification of the residue by kugelrohr distillation
(110°C, 0.35 mbar) afforded 248 mg (79%) of analytically pure
aldehyde 10 as a colourless oil. Ϫ IR (CDCl3): ν˜ ϭ 1705 cmϪ1 (vs),
Hydrogenation of the N-Benzylisoxazolinone 3b, 2-Hydroxy-2-bu-
tenedicarboxylic Acid 4-Benzylamide 1-Methyl Ester (7): According
to Method B, 69 mg (0.30 mmol) of isoxazolinone 3b, 56 mg Pd/
BaSO4 and 10 ml of MeOH. Recrystallization of the crude product
(67 mg) from CH2Cl2/petroleum ether yielded 63 mg (91%) of ana-
1
1670 (s), 1115, 925, 719 (s). Ϫ H NMR (CDCl3, 250 MHz): δ ϭ
3.40 (s, 3 H, OCH3), 5.21 (s, 2 H, NCH2), 5.95 (s, 1 H, 4-H), 9.89
(s, 1 H, CHO). Ϫ 13C NMR (CDCl3, 62.9 MHz): δ ϭ 57.0 (q,
OCH3), 75.6 (t, NCH2O), 100.2 (d, C-4), 168.1 (s, C-5), 173.7 (s,
C-3), 179.3 (d, CHO). Ϫ C6H7NO4 (157.1): calcd. C 45.87, H 4.49,
N 8.91; found C 46.04, H 4.35, N 9.00.
lytically pure benzylamide
7
as colourless crystals, m.p.
131Ϫ132°C. Ϫ IR (KBr): ν˜ ϭ 3335 cmϪ1, 1725, 1635, 1545, 1290,
1240, 985, 765, 725, 682. Ϫ 1H NMR ([D6]acetone, 250 MHz): δ ϭ
3.80 (s, 3 H, OCH3), 4.51 (d, 3J1Ј,NH ϭ 6.0 Hz, 2 H, 1Ј-H), 6.12 (s,
1 H, 3-H), 7.26Ϫ7.37 (m, 5 H, C6H5), 8.1 (br., 1 H, NH), 13.8 (br.,
1 H, 2-OH). Ϫ 13C NMR ([D6]acetone, 62.9 MHz): δ ϭ 43.4 (t,
NCH2Ph), 52.8 (q, OCH3), 98.9 (d, C-3); 128.1, 128.5, 129.4 (3 d,
o-, m-, p-C6H5); 139.9 (s, iC6H5), 163.5 (s, C-1), 171.6 (s, C-4), 203.1
(s, C-2). Ϫ MS (CI, CH4); m/z (%): 264 (10) [Mϩ ϩ C2H5], 236
(100) [Mϩ ϩ H], 176 (20) [Mϩ Ϫ COOMe], 91 (20) [C7H7ϩ]. Ϫ
Ƞ
Dedicated to Professor Waldemar Adam on the occasion of his
60th birthday.
[1]
Taken in part from: [1a] M. Schön, Dissertation, Stuttgart 1997;
Ϫ
[1b] R. Riess, Dissertation, Würzburg, 1993; Ϫ [1c] S. Laschat,
Diplomarbeit, Würzburg, 1987. Preliminary results reported in:
478
Eur. J. Org. Chem. 1998, 473Ϫ479

Short Access to 3-Alkoxyisoxazole-5-carbaldehydes and 3-Hydroxyisoxazole-5-carbaldehyde
FULL PAPER
[1d]
Ϫ
M. Schön, S. Laschat, R. Riess, V. Jäger, 3-Hydroxyisox-
P. Krogsgaard-Larsen, J. Med. Chem. 1985, 28, 668Ϫ672. Ϫ
[10c]
azole-5-carbaldehydes Ϫ Versatile Key Intermediates in the Syn-
P. Krogsgaard-Larsen, L. Brehm, J. S. Johansen, P. Vin-
thesis of New 3-Hydroxyisoxazoles, 5th Blue Danube Sym-
zents, J. Lauridsen, D. R. Curtis, J. Med. Chem. 1985, 28,
[10d]
´
posium on Heterocyclic Chemistry, Casta-Papiernicka, Slovak
673Ϫ679. Ϫ
P. Krogsgaard-Larsen, E. Ø. Nielsen, D. R.
Republic, 14.Ϫ17.6.1995, POϪ56, Proceedings p. 127 and
Curtis, J. Med. Chem. 1984, 27, 585Ϫ591.
[1e]
[11] [11a]
M. Schön, S. Laschat, R. Riess, V. Jäger, New Approach to
J. J. Hansen, B. Nielsen, P. Krogsgaard-Larsen, L. Brehm,
E. Ø. Nielsen, D. R. Curtis, J. Med. Chem. 1989, 32,
2254Ϫ2260. Ϫ [11b] J. J. Hansen, P. Krogsgaard-Larsen, J. Chem.
Soc., Chem. Commun. 1979, 87Ϫ88; J. Chem. Soc., Perkin
Trans. 1 1980, 1826Ϫ1833.
3-Hydroxyisoxazole-5-carbaldehydes Ϫ Key Intermediates in the
Synthesis of New 3-Hydroxyisoxazoles of Pharmacological Inter-
est, Article 059, “1st Electronic Conference on Heterocyclic
Chemistry”, H. S. Rzepa, J. P. Snyder, C. Leach (Eds.); The
Royal Society of Chemistry, 1997, ISBN 0-85404-894-4.
[12]
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