Synthesis of 2,3 and 4,5-dihydro-hydroxy-isoxazoles and isoxazoles under different pH conditions

Article abstract of DOI:10.2174/157017810790533922

Reaction between aryl 1,3-diketoesters 2a-e and hydroxylamine hydrochloride has been investigated under different experimental conditions. Whereas acid conditions gave principally 3,5-isoxazole esters (3a-e), reactions under neutral and basic conditions l

Full text of DOI:10.2174/157017810790533922

32
Letters in Organic Chemistry, 2010, 7, 32-38
Synthesis of 2,3 and 4,5-Dihydro-hydroxy-isoxazoles and Isoxazoles Under
Different pH Conditions
Virginie Andrzejaka, Régis Milleta, Jamal El Bakalia, Abdelhalim Guelzimb, Sebastien Gluszoka,
Philippe Chavattec, Jean-Paul Bonted, Claude Vaccher*,d, Emmanuelle Lipka*,d
aUniversité Lille Nord de France, Institut de Chimie Pharmaceutique Albert Lespagnol, EA2692, IFR114, 3 rue du
Professeur Laguesse BP-83, 59006, Lille, France
bUniversité Lille Nord de France, Laboratoire de Dynamique et de Structure des Matériaux Moléculaires, UPRESA
8024, UFR de Physique, Bâtiment P5, 59655 Villeneuve d’Ascq Cedex France
cUniversité Lille Nord de France, Faculté des Sciences Pharmaceutiques et Biologiques, Laboratoire de Chimie
Thérapeutique, EA1043, IFR114, 3 rue du Professeur Laguesse BP-83, 59006, Lille, France
dUniversité Lille Nord de France, Faculté des Sciences Pharmaceutiques et Biologiques, Laboratoire de Chimie
Analytique, EA4034, IFR114, 3 rue du Pr. Laguesse, BP-83, 59006 Lille, France
Received April 04, 2009: Revised September 22, 2009: Accepted October 14, 2009
Abstract: Reaction between aryl 1,3-diketoesters 2a-e and hydroxylamine hydrochloride has been investigated under
different experimental conditions. Whereas acid conditions gave principally 3,5-isoxazole esters (3a-e), reactions under
neutral and basic conditions led to different 4,5 and 2,3-dihydro-hydroxy-isoxazoles 4a-e and 5a-e.
Keywords: Isoxazoles, dihydro-hydroxy-isoxazoles, aryl 1,3-diketoesters, hydroxylamine.
INTRODUCTION
diketoesters with hydroxylamine under various experimental
conditions.
The isoxazole scaffold has shown considerable interest in
the synthesis of numerous drug candidates: indeed,
compounds containing this five-membered ring exhibit a
broad spectrum of biological activities such as antibacterial
[1, 2], anti-inflammatory [3], or anti-cancer properties [4].
As part of our ongoing research program [5-7] to develop
new derivatives of biological interest we were interested in
the synthesis of 3,5-disubstitued isoxazole bearing an aryl
group in C-5 and an amide function in C-3.
As depicted in Scheme 1, the various arylketones 1a-e
(See Table 1) were oxalylated by diethyl oxalate in the
presence of sodium ethanolate, producing aryl 1,3-
diketoesters 2a-e in high yields in their enol forms.
However, we have noticed that yields varied according to the
electronic nature of the substituent bearing by the aromatic
moiety. Indeed, the best yields were obtained when the
substituent borne by the aromatic moiety possessed an
electronic withdrawing character. Because of their capacity
to increase the acidity of the ketonic protons, withdrawing
substituents are able to increase the electrophilic character of
the ketonic carbone.
To date, numerous synthetic methods have been
described for the preparation of isoxazoles and one of the
most frequently used is a 1,3-dipolar cycloaddition between
an alkyne and a nitrile oxide [8]. Other synthetic methods
involve oxidative aromatization of isoxazolines [9]
preparations from N-acetoacetyl derivatives [10] or 1,1-
disubstitued bromoalkene [11]. The coupling of an appro-
priate non-symmetrical 1,3-diketone with hydroxylamine is
usually described as leading to the formation of two
regioisomers (3,5 and 5,3 isoxazole) during the reaction [12].
In some cases when this reaction is carried out with amines,
the regioselectivity of this reaction can be controlled by
adjusting pH of the reaction medium [13, 14]. Thus, to
develop new anti-inflammatory compounds, we focused
our attention on the coupling of different 1,3-
Treatment of the aryl 1,3-diketoesters 2a-e was next
investigated under three different conditions: i) alkaline
(procedure A), ii) neutral (only with hydroxylammonium
chloride, procedure B), and iii) acid (procedure C). During
the cyclization step, LC/MS analysis showed a M+18 peak,
depending on the pH of the reaction and which could
correspond to different dihydro-hydroxy-isoxazoles.
Synthesis and characterization of such dihydro-hydroxy-
isoxazoles bearing an aryl ring and an ester function have not
been reported thus far. Pei and Wickham [15] have just
indicated that when the reaction is carried out in the presence
of base (Et3N or NaHCO3), the desired isoxazole ester was
obtained in very low yield (<10%). In addition, on similar
compounds, Manning and Coleman [16] revealed that
*Address correspondence to these authors at the Université Lille Nord de
France, Faculté des Sciences Pharmaceutiques et Biologiques, Laboratoire
de Chimie Analytique, EA4034, IFR114, 3 rue du Pr. Laguesse, BP-83,
59006 Lille, France; Tel: +33 (0)3 20 96 47 01; Fax: +33 (0)3 20 95 90 09;
E-mails: claude.vaccher@univ–lille2.fr; emmanuelle.lipka@univ-lille2.fr
condensation of
1 eq. of hydroxylamine with 3,3-
disubstituted 2,4-pentanediones led to 4,5-dihydro-hydroxy-
isoxazoles as a single alcohol. Then, as regards of the
pharmaceutical interest of isoxazole ring, we wished to
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

Synthesis of 2,3 and 4,5-Dihydro-hydroxy-isoxazoles
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
33
Ar =
a : phenyl
O
b : 4-bromophenyl
c : 1-naphthyl
d : 2-naphthyl
Ar
1a-1e
e : 4-trifluoromethylphenyl
O
O
O
O
EtONa / EtOH
O
OH
OEt
O
Ar
2a-2e
(74-99%)
Procedure A
Procedure B
Procedure C
O
O
O
H
N
EtO
N
O
N
EtO
EtO
O
HO
O
OH
Ar
Ar
Ar
3a-3e
5a-5e
4a-4e
Procedure C
Scheme 1. Synthetic pathway for the obtention of isoxazoles and isoxazolines.
Reagents and conditions:
-Procedure A: NH2OH.HCl, DIPEA (3eq), EtOH, reflux, 2h.
-Procedure B: NH2OH.HCl, EtOH reflux, 2h.
-Procedure C: NH2OH.HCl, PTSA, toluene, Dean-Stark conditions, reflux, 2h.
elucidate the structure of such regioisomers and proved that
the reaction can be compatible with different aryl 1,3-
diketoesters. The two different dihydro-hydroxy-isoxazole
rings could constitute an attractive building block in the
design of drug candidates.
electronic effects on the group ester render the position
adjacent to the ester most susceptible to attack by
nucleophiles and effectively, the 3,5-regioisomer was
generated.
Secondly, in order to optimize the cyclization step and to
explain the origin of M+18 peak, three different procedures
were explored. Under alkaline conditions (procedure A), a
mixture of dihydro-hydroxy-isoxazoles and isoxazoles (3a-e)
was obtained. Neutral conditions (procedure B) gave
isoxazole (3a-e) and a single dihydro-hydroxy-isoxazole.
Isoxazoles and dihydro-hydroxy-isoxazoles were purified
and separated by flash-chromatography (cyclohexane /
AcOEt ; 8:2). Reaction between 2a-e and hydroxylamine
hydrochloride with PTSA (procedure C) generated only the
isoxazole esters (3a-e) in good yields (see General Procedure
RESULTS AND DISCUSSION
Firstly, since crystallization of 3a was difficult,
assignment of 3,5-isoxazole ester ring (versus 5,3) was
achieved by crystallographic data obtained on 5-phenyl-N-
(3-phenylpropyl)isoxazole-3carboxamide (6). Thanks to a
recrystalization in absolute ethyl alcohol of this compound
obtained from 3a by a rapid saponification of ester function
followed by a coupling reaction with phenylpropylamine
under peptidic conditions (HOBt, HBTU), the structure was
unambiguously secured by an X-Ray crystal [17] (Fig. 1)
and a NMR 1H analysis. These data confirm that the
1
of Synthesis). The first NMR H analysis of M+18 peak
from the procedure A highlighted the presence of two
compounds which have not been separated by flash

34 Letters in Organic Chemistry, 2010, Vol. 7, No. 1
Andrzejak et al.
min. Some further chromatographic analyses showed that
alcohols were eluted later than the ester isoxazole. It can be
explained by supplementary H-bondings between the alcohol
solute and the stationary phase. CE confirmed results
obtained from HPLC and was run with anionic cyclodextrins
(highly sulfated-ꢀ-CD) as driving selectors. Cyclodextrins
were chosen because of their remarkable ability to form
inclusion complexes with a wide variety of molecules [20,
21]. Analysis was carried out with a 25 mM phosphate
buffer, pH 2.5. The electropherogram obtained for 4a and 5a
(procedure A) presented two peaks at 7.03 and 4.69 min,
respectively (Fig. 3). The alcohol 4a migrated after the
alcohol 5a, as in HPLC. For compound 4a (procedure B),
one peak was observed at 6.92 min. For compound 3a
(procedure B), one peak was observed at 6.80 min and
(procedure C) one peak at 3.65 min.
Fig. (3). UV207nm electropherogram of 4a and 5a alcohols. Fused-
silica capillary coated with PEO 50.2 cm (effective length 10 cm) x
50 ꢀm I.D.; normal polarity, long end; BGE, 25 mM phosphate
buffer pH 2.5 (H3PO4 + TEA) containing 3% of HS-ꢀ-CD;
cathodic injection, 0.5 psi pressure for 5 s of 0.25 mM solution;
applied voltage, 25 kV; temperature, 25 ˚C.
Fig. (1). ORTEP plot of the isoxazole amide 6.
chromatography. Then, to unambiguously determinate the
structure of the obtained products (alcohols 4a and 5a) the
cyclization step was monitored by HPLC and CE. HPLC
analysis was carried out by means of a Daicel Chiralcel OD-
H column [18, 19], with an eluent of hexane/ethanol (90:10).
Following this method, two peaks were obtained on the
chromatogram at 12.55 and 8.90 min, respectively (Fig. 2).
The structure of the isoxazole esters 3a and the two
alcohols 4a and 5a was confirmed by H NMR spectra. The
1
most important difference between alcohols 4a and 5a lies in
the observation of two doublets confirming the presence of
two nonequivalent protons (-CH2-) for 4a and one singulet
showing the presence of one ethylenic proton (-CH=) for 5a.
The rotary power of compounds 4a and 5a also confirmed
that compounds were obtained as racemate.
The procedures A-C were found to be compatible with
different aromatic groups such as 4-bromophenyl, 1-
naphthyl, 2-naphthyl, or 4-trifluorophenyl groups. Then,
procedure A led to mainly 4,5-dihydro-hydroxy-isoxazoles
4a-e (71-93% yields) than 2,3-dihydro-hydroxy-isoxazoles
5a-e (6-24% yields). Compounds 5a, 5c, and 5e were
obtained in the same range (19-24%). Lower yields (6% and
10%) were obtained for 5b and 5d, respectively. Steric and
electronic effects seem to have no influence on the reactivity
and starting material was not recovered. We also observed
the formation of isoxazole (3a-e) with a low yield. Procedure
B furnished principally isoxazoles 3a-d (78-92%) than 4,5-
dihydro-hydroxy-isoxazoles 4a-d (8-22%). An exception
was observed for 3e and 4e where the ratio was 56/44.
Substrate with bromine seems to be less favorable and
reactive for the dehydration step. Finally, procedure C
furnished exclusively 3a-e in 82-95% of isolated yields.
Fig. (2). UV207nm chromatogram of 4a and 5a alcohols. Columm
OD-H 4.6 x 250 mm, 5 ꢀm; mobile phase hexane/ethanol (90:10
v/v); flow-rate, 0.8 ml/min; temperature, 25 ˚C.
The alcohol 4a originally from procedure B was also
analyzed by HPLC and presented a retention times at 12.50
min. For compound 3a (procedure B), one peak was
observed at 6.80 min and (procedure C) one peak at 6.77

Synthesis of 2,3 and 4,5-Dihydro-hydroxy-isoxazoles
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
35
Table 1. Dihydro-hydroxy-isoxazoles 4a-e, 5a-e and 3,5-isoxazole Esters 3a-e Produced Via Scheme 1 from five aryl ꢀ-diketoesters
2a-e
Compounds
Ar
Ratio 3: 4: 5 (Yields %)
NH2OH.HCl
NH2OH.HCl, 3 eq. DIEA
Procedure A
NH2OH.HCl, PTSA
Procedure C
Procedure B
3a, 4a, 5a
3b, 4b, 5b
3c, 4c, 5c
3d, 4d, 5d
3e, 4e, 5e
a = phenyl
b = 4-bromophenyl
c = 1-naphthyl
5 ; 71; 24
1 ; 93; 6
82; 16; 0
85; 15; 0
78; 22; 0
92; 8; 0
95; 0; 0
84; 0; 0
80; 0; 0
90; 0; 0
82; 0; 0
5 ; 76; 19
5 ; 85; 10
5 ; 74; 21
d = 2-naphthyl
e = 4-trifluoromethylphenyl
56; 44; 0
To validate and conclude this study, compounds 4a-e and
5a-e were refluxed in toluene in the presence of PTSA (0.5
equiv) with a Dean-Stark apparatus. After 2h, we observed
only the formation of the 3,5-isoxazole 3a-e.
absolute ethyl alcohol) a solution of aromatic ketone (33.0
mmol, 1 equiv.) and diethyl oxalate (66.0 mmol, 2 equiv.)
was added dropwise at 50°C in 30 mL of absolute ethyl
alcohol. Then, the reaction mixture was heated at reflux for 2
h. At the end of the reaction, solvent was evaporated under
reduced pressure. The residue obtained was diluted with 100
mL of an aqueous solution of hydrochloric acid (1N) and
stirred at room temperature for 1 h. The product was then
extracted with 100 mL of ethyl acetate and washed by 100
mL of distilled water. The organic phase was dried with
MgSO4, filtered and concentrated under reduced pressure.
Next, the residue obtained was triturated with cyclohexane to
give compounds 2a-e.
CONCLUSION
In summary, we have investigated the reaction of
hydroxylamine with a set of aryl 1,3-diketoesters 2a-e and
unambiguously determined the structure of obtained
products under different reactions conditions. The procedure
showed to be compatible with a set of aryl 1,3-diketoesters.
In acid conditions, only the isoxazoles are formed, whereas
in neutral or in alkaline conditions the formation of
isoxazoles is paired of the generation of dihydro-hydroxy-
isoxazoles. We described for the first time characterization
of such compounds. The use of alkaline conditions furnished
a mixture of two 2,3 and 4,5-dihydro-hydroxy-isoxazoles
(5a-e and 4a-e). The same reaction carried with
hydroxylammonium chloride gave only 4,5-dihydro-
hydroxy-isoxazoles (4a-e).
Ethyl 2-hydroxy-4-oxo-4-phenyl-2-butenoate (2a)
Orange oil; 5.45 g (75%). IR (ꢀ, cm–1) 1736 (CO), 1600
1
(enol). H NMR (300 MHz; DMSO): ꢀ 1.12 ppm (t, CH3-
CH2-, 3H, J= 6.4 Hz), 3.98 ppm (q, CH3-CH2-, 2H, J= 6.4
Hz), 7.08 ppm (s, -CH=, 1H), 7.54 ppm (t, ArH, 2H, J= 7.8
Hz), 7.67 ppm (t, ArH, 1H, J= 7.9 Hz), 8.02 (d, ArH, 2H, J=
7.7 Hz), 10.68 ppm (s, -OH, 1H). LC/MS (APCI+) calcd for
C12H12O4, m/z: 221 (MH+).
Ethyl 4-(4-bromophenyl)-2-hydroxy-4-oxo-2-butenoate (2b)
EXPERIMENTAL SECTION
Yellow solid; 7.30 g (74%); Mp 65-66°C. IR (ꢀ, cm–1)
All commercial reagents and solvents were used without
further purification. Analytical thin-layer chromatography
was performed on precoated Kieselgel 60F254 plates
(Merck); the spots were located by UV (254 and 366 nm)
and/or with iodine. Silica gel 60 230-400 mesh purchased
from Merck was used for column chromatography. All
melting points were determined with a Büchi 535 capillary
apparatus and remain uncorrected. The IR spectra were
recorded in a potassium bromide pellet with a Bruker Vector
22 spectrophotometer; absorbances were reported in ꢀ (cm-1).
1H NMR spectra were obtained using a Brücker 300 MHz
spectrometer, chemical shift (ꢁ) were expressed in ppm
relative to tetramethylsilane used as an internal standard, J
values were in hertz, and the splitting patterns were
designated as follow: s singlet, d doublet, t triplet, m
multiplet. All compounds were analyzed by HPLC-MS on a
HPLC combined with a Surveyor MSQ (Thermo Electron)
equipped with an APCI+ source.
1
1721 (CO), 1592 (enol). H NMR (300 MHz; DMSO): ꢀ
1.47 ppm (t, CH3-CH2-, 3H, J= 7.2 Hz), 4.42 (q, CH3-CH2-,
2H, J= 7.2 Hz), 6.99 (s, -CH=, 1H), 7.88-8.07 ppm (m, ArH,
4H), 10.68 ppm (s, -OH, 1H). LC/MS (APCI+) calcd for
C12H11BrO4, m/z: 299 (MH) and 301 (MH)2+.
Ethyl 2-hydroxy-4-(1-naphthyl)-4-oxo-2-butenoate (2c)
Yellow solid; 7.57 g (85%); Mp 61-62°C. IR (ꢀ, cm–1)
1
1728 (CO), 1610 (enol). H NMR (300 MHz; DMSO): ꢀ
1.43 ppm (t, CH3-CH2-, 3H, J= 7.2 Hz), 4.42 ppm (q, CH3-
CH2-, 2H, J= 7.2 Hz), 7.30 ppm (s, -CH=, 1H), 7.52-7.68
ppm (m, ArH, 3H), 7.88-7.97 ppm (m, ArH, 2H), 8.06 ppm
(d, ArH, 1H, J= 8.2 Hz), 8.61 ppm (d, ArH, 1H, J= 8.2 Hz),
10.69 ppm (s, -OH, 1H). LC/MS (APCI+) calcd for
C16H14O4, m/z: 271 (MH)+.
Ethyl 2-hydroxy-4-(2-naphthyl)-4-oxo-2-butenoate (2d)
Yellow solid; 6.59 (74%); Mp 79-80°C. IR (ꢀ, cm–1)
1
1722 (CO), 1601 (enol). H NMR (300 MHz; DMSO): ꢀ
General Procedure for the Synthesis of Ethyl 2-hydroxy-
4-oxo-but-2-enoates (Compounds 2a-e)
1.47 ppm (t, CH3-CH2-, 3H, J= 7.2 Hz), 4.42 ppm (q, CH3-
CH2-, 2H, J= 7.2 Hz), 7.25 ppm (s, -CH=, 1H), 7.55-7.68
ppm (m, ArH, 2H), 7.88-8.07 ppm (m, ArH, 4H), 8.57 ppm
To a solution of freshly prepared sodium ethanolate
(obtained from sodium (66.0 mmol, 2 equiv.) in 50 mL of

36
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
Andrzejak et al.
(s, ArH, 1H), 10.68 ppm (s, -OH, 1H). LC/MS (APCI+)
Ethyl 5-phenyl-3-isoxazolecarboxylate (3a)
calcd for C16H14O4, m/z: 271 (MH)+.
White solid; procedure A: 81 mg (5%), procedure B: 1.32
Ethyl 2-hydroxy-4-oxo-4-[4-(trifluoromethyl)phenyl]-2-
butenoate (2e)
g (82%), procedure C: 1.53 g (95%); Mp 59-60°C. IR (ꢀ,
1
cm–1) 1731 (CO). H NMR (300 MHz; DMSO): ꢀ 1.30 ppm
(t, CH3-CH2-, 3H, J= 7.2 Hz), 4.29 ppm (q, CH3-CH2-, 2H,
J= 7.3 Hz), 7.13 ppm (s, -CH=, 1H), 7.48-7.52 ppm (m,
ArH, 5H). LC/MS (APCI+) calcd for C12H11NO3, m/z: 218
(MH)+.
Yellow solid; 9.40 g (99%); Mp 50-51°C. IR (ꢀ, cm–1)
1
1702 (CO), 1613 (enol). H NMR (300 MHz; DMSO): ꢀ
1.30 ppm (t, CH3-CH2-, 3H, J= 7.3 Hz), 4.19 ppm (q, CH3-
CH2-, 2H, J= 7.3 Hz), 6.98 ppm (s, -CH=, 1H), 7.64 ppm (d,
ArH, 2H, J= 8.2 Hz), 8.02 ppm (d, ArH, 2H, J= 8.2 Hz),
10.68 ppm (s, -OH, 1H). LC/MS (APCI+) calcd for
C13H11F3O4, m/z: 289 (MH)+.
Ethyl 5-(4-bromophenyl)-3-isoxazolecarboxylate (3b)
White solid; procedure A: 0.02 g (1%), procedure B: 1.86
g (85%), procedure C: 1.84 g (84%); Mp 133-134°C. IR (ꢀ,
cm–1) 1725 (CO). 1H NMR (300 MHz; DMSO): ꢀ 1.34 ppm
(t, CH3-CH2-, 3H, J= 7.1 Hz), 4.39 ppm (q, CH3-CH2-, 2H,
J= 7.1 Hz), 7.58 ppm (s, -CH=, 1H), 7.78 ppm (d, ArH, 2H,
J= 8.5 Hz), 7.93 ppm (d, ArH, 2H, J= 8.5 Hz). LC/MS
(APCI+) calcd for C12H10BrNO3, m/z: 296 (MH) and 298
(MH)2+.
General Procedure for the Cyclisation in Alkaline
Conditions, Procedure A (Compounds 3a-e, 4a-e and 5a-
e)
A mixture of compounds 2a-e (7.41 mmol, 1 equiv.),
hydroxylamine hydrochloride (7.41 mmol, 1 equiv.) and
DIPEA (22.2 mmol, 3 equiv.) in 50 mL of absolute ethyl
alcohol was refluxed for 2h. After cooling to room
temperature, the solvent was evaporated and the residue
obtained was purified by flash chromatography (cyclohexane
/ AcOEt ; 8:2).
Ethyl 5-(1-naphthyl)-3-isoxazolecarboxylate (3c)
White solid; procedure A: 102 mg (5%), procedure B:
1.54 g (78%), procedure C: 1.58 g (80%); Mp 64-65°C. IR
1
(ꢀ, cm–1) 1735 (CO). H NMR (300 MHz; DMSO): ꢀ 1.36
ppm (t, CH3-CH2-, 3H, J= 7.2 Hz), 4.43 ppm (q, CH3-CH2-,
2H, J= 7.2 Hz), 7.42 ppm (s, -CH=, 1H), 7.63-7.71 ppm (m,
ArH, 3H), 7.96 ppm (d, ArH, 1H, J= 6.7 Hz), 8.07 ppm (d,
ArH, 1H, J= 7.8 Hz), 8.16 ppm (d, ArH, 1H, J= 8.2 Hz),
8.22 ppm (d, ArH, 1H, J= 7.9 Hz). LC/MS (APCI+) calcd
for C16H13NO3, m/z: 268 (MH)+.
General Procedure for the Cyclisation in Neutral
Conditions, Procedure
Compounds 4a-e)
B
(Compounds 3a-e and
A mixture of compounds 2a-e (7.41 mmol, 1 equiv.) and
hydroxylamine hydrochloride (7.41 mmol, 1 equiv.) in 50
mL of absolute ethyl alcohol was refluxed and stirred for 2h.
After cooling to room temperature, the solvent was
evaporated and the residue obtained was purified by flash
chromatography (cyclohexane / AcOEt; 8:2).
Ethyl 5-(2-naphthyl)-3-isoxazolecarboxylate (3d)
White solid; procedure A: 102 mg (5%), procedure B:
1.82 g (92%), procedure C: 1.78 g (90%); Mp 107-108°C. IR
1
(ꢀ, cm–1) 1718 (CO). H NMR (300 MHz; DMSO): ꢀ 1.36
ppm (t, CH3-CH2-, 3H, J= 7.1 Hz), 4.41 ppm (q, CH3-CH2-,
2H, J= 7.0 Hz), 7.61 ppm (s, -CH=, 1H), 7.62-7.64 ppm (m,
ArH, 2H), 7.98-8.03 ppm (m, ArH, 1H), 8.06-8.11 ppm (m,
ArH, 3H), 8.60 ppm (s, ArH, 1H). LC/MS (APCI+) calcd for
C16H13NO3, m/z: 268 (MH)+.
General Procedure for Dehydration. Procedure
(Compounds 3a-e)
C
(a)
From benzoylpyruvates 2a-e.
compounds 2a-e (7.41 mmol,
A
mixture of
equiv.),
Ethyl 5-[4-(trifluoromethyl)phenyl]-3-isoxazolecarboxylate
(3e)
1
hydroxylamine hydrochloride (7.41 mmol, 1 equiv.)
and PTSA (3.71 mmol, 0.5 equiv) in 50 mL of
toluene was heated at reflux in a Dean-Stark
apparatus for 2h. At the end of reaction, the mixture
was cooled to room temperature, then the solvent was
evaporated. The residue was diluted with 50 mL
dichloromethane and successively washed by 50 mL
of NaHCO3 (5%) and 50 mL of water. The organic
phase was dried with MgSO4, filtered and
concentrated under reduced pressure.
White solid; procedure A: 0.13 g (5%), procedure B: 1.18
g (56%), procedure C: 1.73 g (82%); Mp 136-137°C. IR (ꢀ,
1
cm–1) 1723 (CO). H NMR (300 MHz; DMSO): ꢀ 1.38 ppm
(t, CH3-CH2-, 3H, J= 7.2 Hz), 4.39 ppm (q, CH3-CH2-, 2H,
J= 7.2 Hz), 7.85 ppm (s, -CH=, 1H), 8.36 ppm (d, ArH, 2H,
J= 8.2 Hz), 8.42 ppm (d, ArH, 2H, J= 8.2 Hz). LC/MS
(APCI+) calcd for C13H10F3NO3, m/z: 286 (MH)+.
Ethyl 5-hydroxy-5-phenyl-4,5-dihydro-3-isoxazolecarbo-
xylate (4a)
(b)
From alcohols 4a-4e or 5a-5e. Compounds 4a-4e or
5a-5e (3.54 mmol, 1 equiv.) were refluxed in 30 mL
of toluene in presence of PTSA (1.77 mmol, 0.5
equiv) with Dean-Stark apparatus for 2h. After
cooling to room temperature, toluene was evaporated
and residue diluted with dichloromethane before to be
washed by 30 mL of NaHCO3 (5%), then by 30 mL
of water. The organic phase was dried, filtered and
evaporated.
Colourless oil; procedure A: 1.24 g (71%), procedure B:
0.29 g (16%). IR (ꢀ, cm-1) 1729 (CO), 1125 (C-OH). 1H
NMR (300 MHz; DMSO): ꢀ 1.24 ppm (t, CH3-CH2-, 3H, J=
7.2 Hz), 3.40 ppm (d, -CH2-C(OH)-, 1H, J= 18.1 Hz), 3.85
ppm (d, -CH2-C(OH)-, 1H, J= 18.1 Hz), 4.21 ppm (q, CH3-
CH2-, 2H, J= 7.2 Hz), 7.47 ppm (m, ArH, 3H), 7.71 ppm (m,
ArH, 2H), 7.87 (s, -OH, 1H). LC/MS (APCI+) calcd for
C12H13NO4, m/z: 236 (MH)+.

Synthesis of 2,3 and 4,5-Dihydro-hydroxy-isoxazoles
Letters in Organic Chemistry, 2010, Vol. 7, No. 1
37
Ethyl 5-(4-bromophenyl)-5-hydroxy-4,5-dihydro-3-isoxazo-
lecarboxylate (4b)
1.23 ppm (t, CH3-CH2-, 3H, J= 7.2 Hz), 4.19 ppm (q, CH3-
CH2-, 2H, J= 7.2 Hz), 4.26 ppm (s, -CH=, 1H), 7.39 ppm (d,
ArH, 2H, J= 8.2 Hz), 7.89 ppm (s, -OH, 1H), 8.00 (d, ArH,
2H, J= 8.2 Hz), 12.55 (s, -NH, 1H). LC/MS (APCI+) calcd
for C12H12BrNO4, m/z: 314 (MH) and 316 (MH)2+.
Colourless oil; procedure A: 2.16 g (93%), procedure B:
0.35 g (15%). IR (ꢀ, cm-1) 1725 (CO), 1134 (C-OH). 1H
NMR (300 MHz; DMSO): ꢀ 1.26 ppm (t, CH3-CH2-, 3H, J=
7.2 Hz), 3.44 ppm (d, -CH2-C(OH)-, 1H, J= 18.2 Hz), 3.91
ppm (d, -CH2-C(OH)-, 1H, J= 18.2 Hz), 4.22 ppm (q, CH3-
CH2-, 2H, J= 7.2 Hz), 7.48 ppm (d, ArH, 2H, J= 8.2 Hz),
7.71 ppm (d, ArH, 2H, J= 8.2 Hz), 7.86 (s, -OH, 1H).
LC/MS (APCI+) calcd for C12H12BrNO4, m/z: 314 (MH) and
316 (MH)2+.
Ethyl 3-hydroxy-5-(1-naphthyl)-2,3-dihydro-3-isoxazole-
carboxylate (5c)
Colourless oil; procedure A: 0.40 g (19%). IR (ꢀ, cm-1)
1726 (CO), 1135 (C-OH). 1H NMR (300 MHz; DMSO): ꢀ
1.27 ppm (m, CH3-CH2-, 3H), 4.22 ppm (q, CH3-CH2-, 2H,
J= 7.2 Hz), 4.25 (s, -CH=, 1H), 7.39-7.42 ppm (m, ArH,
3H), 7.54 ppm (d, ArH, 1H, J= 7.1 Hz), 7.64 ppm (d, ArH,
1H, J= 8.2 Hz), 7.66 ppm (d, ArH, 1H, J= 7.9 Hz), 7.90 (s, -
NH, 1H), 8.02 ppm (d, ArH, 1H, J= 8.2 Hz) 12.54 (s, -OH,
1H). LC/MS (APCI+) calcd for C16H15NO4, m/z: 286
(MH)+.
Ethyl 5-hydroxy-5-(1-naphthyl)-4,5-dihydro-3-isoxazole-
carboxylate (4c)
Colourless oil; procedure A: 1.61 g (76%), procedure B:
0.46 g (22%). IR (ꢀ, cm-1) 1722 (CO), 1120 (C-OH). 1H
NMR (300 MHz; DMSO): ꢀ 1.22 ppm (t, CH3-CH2-, 3H, J=
7.2 Hz), 3.32 ppm (d, -CH2-C(OH)-, 1H, J= 18.2 Hz), 3.85
ppm (d, -CH2-C(OH)-, 1H, J= 18.2 Hz), 4.20 ppm (q, CH3-
CH2-, 2H, J= 7.2 Hz), 7.46-7.51 ppm (m, ArH, 3H), 7.56
ppm (d, ArH, 1H, J= 7.0 Hz), 7.59 ppm (d, ArH, 1H, J= 7.9
Hz), 7.68 ppm (d, ArH, 1H, J= 8.2 Hz), 7.71 ppm (d, ArH,
1H, J= 7.9 Hz) 7.87 (s, -OH, 1H). LC/MS (APCI+) calcd for
C16H15NO4, m/z: 286 (MH)+.
Ethyl 3-hydroxy-5-(2-naphthyl)-2,3-dihydro-3-isoxazole-
carboxylate (5d)
Colourless oil; procedure A: 0.21 (10%). IR (ꢀ, cm-1)
1724 (CO), 1152 (C-OH). 1H NMR (300 MHz; DMSO): ꢀ
1.23 ppm (m, CH3-CH2-, 3H), 4.18 ppm (q, CH3-CH2-, 2H,
J= 7.2 Hz), 4.29 (s, -CH=, 1H), 7.39-7.51 ppm (m, ArH,
2H), 7.54-7.56 ppm (m, ArH, 1H), 7.61-7.65 ppm (m, ArH,
3H), 7.89 ppm (s, -NH, 1H), 8.00 (s, ArH, 1H), 12.55 ppm
(s, -OH, 1H). LC/MS (APCI+) calcd for C16H15NO4, m/z:
286 (MH)+.
Ethyl 5-hydroxy-5-(2-naphthyl)-4,5-dihydro-3-isoxazole-
carboxylate (4d)
Colourless oil; procedure A: 1.79 g (85%), procedure B:
0.17 g (8%). IR (ꢀ, cm-1) 1726 (CO), 1154 (C-OH). 1H NMR
(300 MHz; DMSO): ꢀ 1.24 ppm (t, CH3-CH2-, 3H, J= 7.2
Hz), 3.38 ppm (d, -CH2-C(OH)-, 1H, J= 18.2 Hz), 3.79 ppm
(d, -CH2-C(OH)-, 1H, J= 18.2 Hz), 4.20 ppm (q, CH3-CH2-,
2H, J= 7.2 Hz), 7.46-7.54 ppm (m, ArH, 2H), 7.68-7.70 ppm
(m, ArH, 1H), 7.71-7.73 ppm (m, ArH, 3H), 7.75 ppm (s,
ArH, 1H), 7.88 (s, -OH, 1H). LC/MS (APCI+) calcd for
C16H15NO4, m/z: 286 (MH)+.
Ethyl 3-hydroxy-5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-
3-isoxazolecarboxylate (5e)
Colourless oil; procedure A: 0.48 (21%). IR (ꢀ, cm-1)
1
1728 (CO), 1154 (C-OH). H NMR (300 MHz; DMSO): ꢀ
1.29 ppm (t, CH3-CH2-, 3H, J= 7.2 Hz), 4.17 ppm (q, CH3-
CH2-, 2H, J= 7.2 Hz), 4.28 (s, -CH=, 1H), 7.54 ppm (d,
ArH, 2H, J= 8.2 Hz), 7.89 (s, -NH, 1H), 8.02 ppm (d, ArH,
2H, J= 8.2 Hz), 12.54 ppm (s, -OH, 1H). LC/MS (APCI+)
calcd for C13H12F3NO4, m/z: 303 (MH)+.
Ethyl 5-hydroxy-5-[4-(trifluoromethyl)phenyl]-4,5-dihydro-
3-isoxazolecarboxylate (4e)
Colourless oil; procedure A: 1.65 g (74%), procedure B:
ABBREVIATIONS
1
0.98 g (44%). IR (ꢀ, cm-1) 1730 (CO), 1156 (C-OH). H
DIPEA = diisopropylethylamine
PTSA = paratoluene sulfonic acid
NMR (300 MHz; DMSO): ꢀ 1.27 ppm (t, CH3-CH2-, 3H, J=
7.2 Hz), 3.44 ppm (d, -CH2-C(OH)-, 1H, J= 18.1 Hz), 3.91
ppm (d, -CH2-C(OH)-, 1H, J= 18.1 Hz), 4.25 ppm (q, CH3-
CH2-, 2H, J= 7.2 Hz), 7.48 ppm (d, ArH, 2H, J= 8.2 Hz),
7.71 ppm (d, ArH, 2H, J= 8.2 Hz), 7.86 (s, -OH, 1H).
LC/MS (APCI+) calcd for C13H12F3NO4, m/z: 303 (MH)+.
ACKNOWLEDGEMENT
This work was financially supported by the Conseil
Régional Nord-Pas de Calais.
Ethyl 3-hydroxy-5-phenyl-2,3-dihydro-3-isoxazolecar-
boxylate (5a)
Colourless oil; procedure A: 0.42 g (24%). IR (ꢀ, cm-1)
1724 (CO), 1112 (C_OH). H NMR (300 MHz; DMSO): ꢀ
1.22 ppm (m, CH3-CH2-, 3H), 4.18 ppm (q, CH3-CH2-, 2H,
J= 7.2 Hz), 4.28 ppm (s, -CH=, 1H), 7.38-7.90 ppm (m,
ArH, 4H), 7.89 (s, -OH, 1H), 7.98 ppm (d, ArH, 1H, J= 7.2
Hz), 12.55 (s, -NH, 1H). LC/MS (APCI+) calcd for
C12H13NO4, m/z: 236 (MH)+.
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