5-Hydroxy-3-phenyl-5-vinyl-2-isoxazoline and 3-phenyl-5-vinylisoxazole: Synthesis and reactivity

Article abstract of DOI:10.1016/j.tet.2005.08.077

5-Hydroxy-3-phenyl-5-vinyl-2-isoxazoline has been synthesized by reacting benzonitrile oxide with the enolate ion of methyl vinyl ketone. From 5-hydroxy-5-vinyl-2-isoxazoline, 5-vinylisoxazole was then quantitatively obtained by dehydration-aromatization

Full text of DOI:10.1016/j.tet.2005.08.077

Tetrahedron 61 (2005) 11270–11278
5-Hydroxy-3-phenyl-5-vinyl-2-isoxazoline and
3-phenyl-5-vinylisoxazole: synthesis and reactivity
*
Leonardo Di Nunno, Antonio Scilimati and Paola Vitale
`
Dipartimento Farmaco-Chimico, Universita degli Studi di Bari, Via E.Orabona 4, 70125 Bari, Italy
Received 30 May 2005; revised 4 August 2005; accepted 18 August 2005
Available online 29 September 2005
Abstract—5-Hydroxy-3-phenyl-5-vinyl-2-isoxazoline has been synthesized by reacting benzonitrile oxide with the enolate ion of methyl
vinyl ketone. From 5-hydroxy-5-vinyl-2-isoxazoline, 5-vinylisoxazole was then quantitatively obtained by dehydration–aromatization under
acidic conditions. Similar results, though not quantitative, were also found by treatment in 2-propanol under basic conditions (i-PrOH/H2O,
Na2CO3, reflux). In contrast to 2-propanol, reactions performed in methanol (and, in part, those carried out in ethanol) revealed a more
complex behaviour, the nucleophilic addition of ROH onto the vinyl group being mainly observed. Nucleophilic addition was also found with
alkyllithiums. The mechanism of the nucleophilic addition is discussed. Epoxidation and further reaction with benzonitrile oxide of both
3-hydroxy-5-phenyl-5-vinyl-2-isoxazoline and 3-phenyl-5-vinylisoxazole are also described.
q 2005 Elsevier Ltd. All rights reserved.
It is well-known that isoxazolines and isoxazoles are
interesting heterocycles from both a synthetic and biological
point of view.1–3 As for the synthetic utility, they are
masked forms of iminoalcohols and iminocarbonyls. The
latter compounds, in fact, can readily and selectively be
obtained by reductive cleavage of the N–O bond using
various methods.4
(or 3,4-diaryl)-5-alkyl (or 5-unsubstituted) isoxazoles
(2a–c) have been synthesized.
We found8,9 that some of the above compounds (2c), as
analogues of Valdecoxib (3, Fig. 1),10 were endowed with
cyclooxygenase inhibitory activity and that 3-(5-chloro-2-
furyl)-5-methyl-4-phenylisoxazole (4, Fig. 1) tested in
human whole blood (HWB) assay11 was a selective and
highly potent COX-1 inhibitor, which could represent
an interesting tool in order to study the involvement of
COX-1 in atherosclerosis,12,13 pain14 and cancer
development.15
The synthesis of both isoxazolines and isoxazoles by new
and more efficient procedures has been the goal of a number
of our previous investigations. Concerning the synthesis of
5-hydroxy-2-isoxazolines, we developed a new efficient
methodology consisting in the cycloaddition of various
enolate ions (including the enolate ion of acetaldehyde) with
arylnitrile oxides.5–7 From these, the corresponding isox-
azoles were then obtained in high yields by simple
dehydration–aromatization under acidic or basic
conditions (Scheme 1). By this procedure various 3-aryl-
Figure 1.
Furthermore, concerning 3-aryl-5-alkylisoxazoles, the
possibility of side-chain elongation by a-metallation
followed by reaction with electrophiles (CH3I, PhCH2Br)
has also been ascertained. Thus, by this procedure, a number
of other isoxazole derivatives can be obtained.6
Scheme 1.
Keywords: Vinylisoxazolines; Vinylisoxazoles; Nucleophilic additions.
*
Corresponding author. Tel.: C39 80 5442734; fax: C39 80 5442231;
e-mail: dinunno@farmchim.uniba.it
On the other hand, concerning the elongation (and/or
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.077

L. Di Nunno et al. / Tetrahedron 61 (2005) 11270–11278
11271
elaboration) of the C5 side-chain in order to obtain more
complex isoxazole derivatives, wider possibilities could in
principle be expected starting from 5-vinyl- instead of
5-alkyl-derivatives. The vinyl group can be extended (or
elaborated) at both the vinyl carbons, including the
possibility of a further cyclization allowing the construction
of an additional homo- or heterocyclic moiety.
same reaction is performed at room temperature and in the
absence of LDA.18 Subsequent dehydration of 5-hydroxy-3-
phenyl-5-vinyl-2-isoxazoline (7) under acidic conditions
(BF3$Et2O) gave quantitatively 3-phenyl-5-vinylisoxazole
(9) (Scheme 4).
Dehydration of 7 in methanol under basic conditions
(Na2CO3, MeOH/H2O, reflux), previously successfully
used for obtaining 3-aryl-5-alkylisoxazoles (2b) from
5-alkyl-3-aryl-5-hydroxy-2-isoxazolines (1b),6 showed
instead a more complex behaviour. Together with the
expected 3-phenyl-5-vinylisoxazole (9), large amounts of
the products of nucleophilic addition of MeOH to the vinyl
group of both 5-hydroxy-5-vinyl-2-isoxazoline and 5-vinyl-
isoxazole (10a and 11a, respectively) were isolated
(Scheme 5 and Table 1).
As for the synthesis of some 3-substituted-5-vinylisoxa-
zoles, some procedures have so far been reported.16,17 In
particular, concerning a 3-aryl-derivative, namely 3-(4-
hydroxyphenyl)-5-vinylisoxazole (6), the synthesis was
accomplished by C5 side-chain elaboration of 5-formyl
isoxazole (Scheme 2). In this way 6 was obtained in 76%
yield.17
Table 1. Products of reaction of 5-hydroxy-3-phenyl-5-vinyl-2-isoxazoline
(7) with ROH/Na2CO3 (Scheme 5)
ROH
Time (h)
9 (%)a
10 (%)a
11 (%)a
MeOH
EtOH
i-PrOH
1
2
2
19
65
48
38 (10a)
—
—
43 (11a)
24 (11b)
—
a Yields refer to the products actually isolated by chromatography.
A relative decrease of nucleophilic addition compared to
dehydration was observed in ethanol. Only the dehydrated
product of the nucleophilic addition (11b) was isolated in
this case. No alcohol addition but only dehydration to
vinylisoxazole 9 was finally observed using isopropanol as
solvent.
Scheme 2.
We explored, instead, the possibility of extending the same
procedure successfully developed by us for 3-aryl-5-
alkylisoxazoles to the synthesis of 5-vinyl-derivatives.
Thus, we reacted benzonitrile oxide with the enolate ion
from methyl vinylketone and LDA (K78 8C), obtaining the
expected 5-hydroxy-3-phenyl-5-vinyl-2-isoxazoline (7) in
high yield (90%) together with a little amount (10%) of
5-acetyl-3-phenyl-2-isoxazoline (8) deriving from the
cycloaddition to the vinyl C]C bond (Scheme 3). In
contrast, it is known that the latter is the only product if the
On the other hand, concerning the products of nucleophilic
addition of MeOH, while compound 10a should actually be
formed from 5-hydroxy-5-vinyl-2-isoxazoline 7, we could
instead demonstrate that 11a is not correspondingly formed
from vinylisoxazole 9. By directly reacting the latter with
MeOH/Na2CO3 under the same conditions, no reaction at all
is in fact observed. Partial addition of MeOH to 3-phenyl-5-
vinylisoxazole 9 could be obtained only by using sodium
methoxide in methanol and more prolonged times of
reaction (Scheme 6).
Thus, by excluding the direct involvement of 3-phenyl-5-
vinylisoxazole (9), the alternative possibility is that 11a is
formed by partial dehydration–aromatization of 10a, so that
the alcohol addition should only concern hydroxyisoxazo-
line 7 in all cases (Scheme 7).
Scheme 3.
On the other hand, concerning the mechanism of the alcohol
addition to 5-hydroxy-3-phenyl-5-vinyl-2-isoxazoline, the
possible pathways are depicted in Scheme 8.
Scheme 4.
Scheme 5.

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L. Di Nunno et al. / Tetrahedron 61 (2005) 11270–11278
As for the apparent order of reactivity of alcohols (MeOHO
EtOH; no addition but only dehydration–aromatization to
vinylisoxazole in the case of i-PrOH), which is opposite
compared to the known reactivity sequence of alcoholates
with enones (i-PrOKOMeOK),19 it should not be in
contrast with the above hypothesis. Taking into account
the used conditions (ROH/Na2CO3), and as also previously
reported for alcohol addition to enones under competitive
conditions,20 the order of reactivity could in fact just be
determined in our case by the alcohol acidity instead of the
alcoholate nucleophilicity.
Scheme 6.
On the other hand, unlike reactions with alcohols, Path 1
seems instead more reasonable in reactions of the
hydroxyvinylisoxazoline with alkyllithiums (MeLi,
n-BuLi).
Path 1, i.e., direct nucleophilic addition to hydroxy-
isoxazoline anion 12 (or to alcohol 7) should involve ring-
opening in order to satisfactorily delocalize the negative
charge introduced by the nucleophile.
In this case, due to the used aprotic solvents, the rate of ring-
chain equilibration should in fact be low compared to
reactions with ROH, thus making more difficult the
alternative Path 2. Further, both products A and B (17 and
18, respectively, the latter no further converted into the
corresponding isoxazole, as the dehydration–aromatization
of hydroxyisoxazolines is made difficult in the presence of
strong bases),5 are isolated (Scheme 9), B being also the
major product in the case of n-BuLi (Table 2). And this
could in fact just be consistent with Path 1, while should be a
rather unusual result if Path 2 was involved, as it is known
On the other hand, ring-opening of hydroxyisoxazoline can
also occur spontaneously and rapidly (ring-chain tautomer-
ism),19 in hydroxylic solvents. This also means, in our case,
fast equilibration with little amounts of a,b-unsaturated
ketone 13. So, taking into account the well-known ability of
conjugated enones to undergo nucleophilic additions by
alcohols,20 Path 2 is also possible. According to this
hypothesis, the products of sole conjugate addition B (in
part or completely converted into the corresponding
isoxazoles by subsequent dehydration–aromatization) are,
as expected for alcohol additions, the only isolated adducts.
Scheme 7.
Scheme 8.

L. Di Nunno et al. / Tetrahedron 61 (2005) 11270–11278
11273
molecule of vinylisoxazole (Scheme 10). Further investi-
gations are in progress on this point.
Finally, unlike the reactions with nucleophiles, a more
similar behaviour could instead be expected by subjecting
both vinylhydroxyisoxazoline 7 and vinylisoxazole 9 to
reactions at the vinyl group not directly involving the
adjacent ring.
Accordingly, not very different results were observed both
in the epoxidation reaction with m-CPBA (Scheme 11) and
in the reaction with benzonitrile oxide generating an
additional isoxazoline ring (Scheme 12).
Scheme 9.
that alkyllithiums generally add to conjugated enones
directly21 (addition to the carbonyl carbon with formation
of product A).
Scheme 11.
On the other hand, at variance with Na2CO3/MeOH (or even
MeOK/MeOH), alkyllithiums are able to completely react
also with 5-vinylisoxazole 9. The main isolated product
under these conditions (reaction with n-BuLi) is not,
however, 19, corresponding to the ‘simple’ nucleophilic
addition to the vinyl group, but 20, involving also a second
Table 2. Products of reaction of 5-hydroxy-3-phenyl-5-vinyl-2-isoxazoline
(7) with RLi (Scheme 9)
RLi
17a–b (%)a
18a–b (%)a
Scheme 12.
MeLi
n-BuLi
75
29
23
65
For either epoxidation by m-CPBA22 or cycloaddition of
nitrile oxides2 a concerted mechanism should in fact operate
(concerning the latter reaction a stepwise mechanism has
only been hypothesized in the case of species like enolate
ions),5 so that both reactions, just as expected, seem to
proceed similarly for hydroxyvinylisoxazoline 7 as well as
for isoxazole 9.
a Yields refer to the products actually isolated by chromatography.
Further investigations aimed to the synthetic exploitation of
compounds 21–24 (Schemes 11 and 12) are in progress.
2. Experimental
2.1. General methods
Melting points taken on Electrothermal apparatus were
uncorrected. H NMR spectra were recorded on a Varian-
1
Mercury 300 MHz spectrometer and chemical shifts are
reported in parts per million (d). Absolute values of the
coupling constant are reported. FT-IR spectra were recorded
on a Perkin–Elmer 681 spectrometer. GC analyses were
Scheme 10.

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L. Di Nunno et al. / Tetrahedron 61 (2005) 11270–11278
performed by using a HP1 column (methyl siloxane; 30 m!
0.32 mm!0.25 mm film thickness) on a HP 6890 model,
Series II. Thin-layer chromatography (TLC) was performed
on silica gel sheets with fluorescent indicator, the spots on
the TLC were observed under ultraviolet light or were
visualized by I2 vapour. Chromatography was conducted by
using silica gel 60 with a particle size distribution 40–63 mm
and 230–400 ASTM. GC–MS analyses were performed on
an HP 5995C model and microanalyses on an Elemental
Analyzer 1106-Carlo Erba-instrument. MS-ESI analyses
were performed on an Agilent 1100 LC/MSD trap system
VL.
int.): 189 (MC, 24), 188 (23), 172 (39), 171 (33), 144 (44),
143 (12), 117 (49), 116 (11), 103 (23), 77 (62), 55 (100), 51
(22). Anal. Calcd for C11H11NO2: C, 69.83; H, 5.86; N,
7.40. Found: C, 69.80; H, 5.84; N, 7.42.
2.4. Synthesis of 3-phenyl-5-vinylisoxazole (9)
To a solution of 5-hydroxy-3-phenyl-5-vinyl-2-isoxazoline
(7) (3.86 g, 20.43 mmol) in freshly distilled CH2Cl2
(100 mL) kept at room temperature, BF3$Et2O (2.6 mL,
20.43 mmol) was added. The reaction mixture was stirred
for 1 h and then quenched by adding water. The reaction
product was extracted three times with CH2Cl2. The organic
phase was dried over anhydrous Na2SO4 and then
evaporated under reduced pressure.
2.2. Materials
Commercially available tetrahydrofuran (THF) was dis-
tilled (twice) from sodium wire under nitrogen. Standard-
ized 1.6 M methyllithium in diethyl ether and 2.5 M
n-butyllithium in hexane was purchased from Aldrich
Chemical Co. Titration of n-butyllithium was performed
by using N-pivaloyl-o-toluidine.23 Methyl vinyl ketone was
2.4.1. 3-Phenyl-5-vinylisoxazole (9). The title compound
was obtained in quantitative yield (3.5 g) by crystallization
(hexane). Mp 39–40 8C (hexane, lit.13 37–38 8C), white
crystals. FT-IR (KBr): 3029, 2917, 2849, 1560, 1466, 1443,
1404, 1278, 926, 767, 692 cmK1. 1H NMR (CDCl3, d): 5.59
(dd, 1H, JZ0.8, 11.4 Hz); 6.06 (dd, 1H, JZ0.8, 17.7 Hz);
6.51 (s, 1H); 6.66 (dd, 1H, JZ17.7, 11.4 Hz); 7.43–7.48 (m,
3H, aromatic protons); 7.79–7.85 (m, 2H, aromatic protons).
13C NMR (75 MHz, CDCl3, d): 99.7, 120.9, 122.6, 127.0,
129.1, 130.2, 162.9, 169.0. GC–MS (70 eV) m/z (rel int.):
171 (MC, 95), 145 (10), 144 (100), 143 (35), 117 (29), 116
(22), 115 (11), 89 (14), 77 (47), 63 (11), 55 (34), 51 (22).
Anal. Calcd for C11H9NO: C, 77.17; H, 5.30; N, 8.18.
Found: C, 77.20; H, 5.29; N, 8.20.
˚
dried over molecular sieves (4 A) just prior to use.
Benzonitrile oxide was prepared by treatment of benzo-
hydroximinoyl chloride with Et3N.5 All other chemicals and
solvents were commercial grade further purified prior to
use.
2.3. Synthesis of 5-hydroxy-3-phenyl-5-vinyl-2-isoxazo-
line (7)
A 2.25 M solution of n-butyllithium in hexane (15.8 mL,
35.48 mmol) was dropwise added to diisopropylamine
(5 mL, 35.48 mmol) in THF (30 mL) at 0 8C under nitrogen
atmosphere, using a nitrogen-flushed three necked flask
equipped with a magnetic stirrer, nitrogen inlet and two
dropping funnels. The mixture was stirred for 15 min at 0 8C
and then cooled to K78 8C. To LDA so formed, the methyl
vinyl ketone (2.95 mL, 35.48 mmol) in THF (80 mL) was
dropwise added. The reaction mixture was stirred at K78 8C
for 1 h and then the benzonitrile oxide (32.25 mmol) in THF
(80 mL) was added. The reaction mixture was stirred at
K78 8C for 1 h and then quenched by adding aqueous
NH4Cl solution. The reaction products were extracted three
times with ethyl acetate. The organic phase was dried over
anhydrous Na2SO4 and then the solvent evaporated under
2.5. Reaction of 5-hydroxy-3-phenyl-5-vinyl-2-isoxazo-
line (7) with Na2CO3 in MeOH/H2O
A solution of Na2CO3 (155 mg, 1.46 mmol) in water
(10 mL) was added to 5-hydroxy-3-phenyl-5-vinyl-2-isox-
azoline 7 (138 mg, 0.73 mmol) in MeOH (10 mL) contained
in a round bottom flask equipped with magnetic stirrer. The
reaction mixture was then refluxed for 1 h. The MeOH was
evaporated under reduced pressure and aqueous layer was
extracted three times with CH2Cl2. The combined organic
extracts were dried over anhydrous Na2SO4 and the solvent
was evaporated under reduced pressure. Column chroma-
tography (silica gel, petroleum ether/ethyl acetateZ8:2) of
the residue affords 5-(2-methoxyethyl)-3-phenylisoxazole
(11a) in 43% yield (Scheme 3), 5-hydroxy-5-(2-methox-
yethyl)-3-phenyl-2-isoxazoline (10a) in 38% yield and
3-phenyl-5-vinylisoxazole (9) in 19% yield.
1
reduced pressure. H NMR of the crude mixture contained
the products 7 and 8 in the ratio 90:10. Column
chromatography (silica gel, petroleum ether/ethyl acetateZ
8:2) of the residue affords the 5-hydroxy-3-phenyl-5-vinyl-
2-isoxazoline (7) in 74% yield (Table 1), and 10% of
5-acetyl-3-phenyl-2-isoxazoline (8).18
2.5.1. 5-Hydroxy-5-(2-methoxyethyl)-3-phenyl-2-isoxa-
zoline (10a). Yield 38% (61 mg). Oil. FT-IR (KBr):
3600–3150, 3030, 2924, 2853, 1620, 1447, 1361, 1208,
1114, 916, 853, 761, 693 cmK1. 1H NMR (CDCl3, d): 2.02–
2.09 (m, 1H); 2.40–2.50 (m, 1H); 3.23 (d, 1H, JZ17.3 Hz,
isoxazoline ring proton); 3.34 (d, 1H, JZ17.3 Hz, isoxazo-
line ring proton); 3.43 (s, 3H); 3.65–3.70 (m, 1H); 3.99–4.06
(m, 1H); 5.35 (s, 1H, OH: exchanges with D2O); 7.35–7.50
(m, 3H, aromatic protons); 7.63–7.68 (m, 2H, aromatic
protons). 13C NMR (75 MHz, CDCl3, d): 37.6, 46.3, 59.4,
69.6, 108.5, 126.8, 128.9, 129.9, 130.3, 157.6. GC–MS
(70 eV) m/z (rel int.): 221 (MC, 5), 204 (17), 203 (65), 189
(4), 173 (9), 162 (13), 144 (12), 135 (17), 134 (13), 117 (38),
103 (28), 87 (20), 77 (40), 51 (14), 45 (100). Anal. Calcd for
2.3.1. 5-Hydroxy-3-phenyl-5-vinyl-2-isoxazoline (7).
Yield 74% (4.5 g). Mp 88–89 8C (ethyl ether/hexane),
white crystals. FT-IR (KBr): 3600–3200, 3060, 2955, 2918,
2849, 1560, 1446, 1359, 1235, 1104, 919, 761, 691 cmK1
.
1H NMR (CDCl3, d): 3.33 (d, 1H, JZ17.3 Hz); 3.40 (d, 1H,
JZ17.3 Hz); 3.50–3.60 (br s, 1H, OH: exchanges with
D2O); 5.37 (dd, 1H, JZ0.8, 10.7 Hz); 5.67 (dd, 1H, JZ0.8,
17.3 Hz); 6.16 (dd, 1H, JZ17.3, 10.7 Hz); 7.35–7.44 (m,
3H, aromatic protons); 7.61–7.69 (m, 2H, aromatic protons).
13C NMR (75 MHz, CDCl3, d): 46.5, 106.5, 117.9, 127.0,
129.0, 129.4, 130.6, 136.5, 157.7. GC–MS (70 eV) m/z (rel

L. Di Nunno et al. / Tetrahedron 61 (2005) 11270–11278
11275
C12H15NO3: C, 65.14; H, 6.83; N, 6.33. Found: C, 65.15; H,
6.83; N, 6.32.
2.8. Reaction of 5-hydroxy-3-phenyl-5-vinyl-2-isoxazo-
line (7) with MeLi
A 1.6 M solution of MeLi in ethyl ether (5.786 mL,
9.26 mmol) was added to a solution of 5-hydroxy-3-
phenyl-5-vinyl-2-isoxazoline (7) (350 mg, 1.852 mmol) in
THF (18 mL) kept at 0 8C under nitrogen, using a nitrogen-
flushed two necked flask equipped with a magnetic stirrer
and a nitrogen inlet. The obtained red reaction mixture was
stirred for 3 h at 0 8C before to add aq NH4Cl. The two
phases were separated and aqueous layer was extracted
three times with EtOAc. The combined organic extracts
were dried over anhydrous Na2SO4 and then the solvent
evaporated under reduced pressure. Column chromato-
graphy (silica gel, petroleum ether/ethyl acetateZ7:3) of
the residue afforded 5-hydroxy-3-phenyl-5-propyl-2-isoxa-
zoline (18a)6 in 23% yield and 3-hydroxy-3-methyl-1-
phenylpent-4-en-1-one oxime (17a) in 75% yield (Scheme 6
and Table 1).
2.5.2. 5-(2-Methoxyethyl)-3-phenylisoxazole (11a). Yield
43% (63 mg). Oil. FT-IR (KBr): 3127, 3053, 2927, 1603,
1
1580, 1471, 1443, 1408, 1117, 914, 769, 694 cmK1. H
NMR (CDCl3, d): 3.07 (t, 2H, JZ6.4 Hz); 3.39 (s, 3H); 3.73
(t, 2H, JZ6.4 Hz); 6.40 (s, 1H); 7.40–7.48 (m, 3H, aromatic
protons); 7.76–7.84 (m, 2H, aromatic protons). 13C NMR
(75 MHz, CDCl3, d): 27.9, 59.0, 69.8, 100.2, 127.0, 129.1,
129.5, 130.1, 162.7, 171.3. GC–MS (70 eV) m/z (rel int.):
203 (MC, 100), 173 (21), 144 (24), 130 (7), 118 (9), 116 (9),
103 (5), 89 (10), 77 (30), 63 (5), 51 (12), 45 (92). Anal.
Calcd for C12H13NO2: C, 70.92; H, 6.45; N, 6.89. Found: C,
70.92; H, 6.44; N, 6.90.
2.6. Reaction of 5-hydroxy-3-phenyl-5-vinyl-2-isoxazo-
line (7) with Na2CO3 in EtOH/H2O
A solution of Na2CO3 (861 mg, 8.12 mmol) in water
(80 mL) was added to 5-hydroxy-3-phenyl-5-vinyl-2-isox-
azoline 7 (769 mg, 4.06 mmol) in EtOH (80 mL) contained
in a round bottom flask equipped with a magnetic stirrer.
The reaction mixture was then refluxed for 2 h. The EtOH
was evaporated under reduced pressure and aqueous layer
was extracted three times with CH2Cl2. The combined
organic extracts were dried over anhydrous Na2SO4 and the
solvent was evaporated under reduced pressure. Column
chromatography (silica gel, petroleum ether/ethyl acetateZ
7:3) of the residue affords 3-phenyl-5-vinylisoxazole 9 in
65% yield and 5-(2-ethoxyethyl)-3-phenylisoxazole 11b in
24% yield (Table 1).
2.8.1. 3-Hydroxy-3-methyl-1-phenylpent-4-en-1-one
oxime (17a). Yield 75% (284 mg). Yellow oil. FT-IR
(CHCl3, 0.09 M): 3693, 3579, 3500–3100, 3028, 2969,
2932, 2876, 1602, 1448, 1361, 1111, 994, 944, 910 cmK1
.
1H NMR (CDCl3, d): 1.27 (s, 3H); 3.00–3.20 (br s, 1H, OH:
exchanges with D2O); 3.17 (s, 2H); 4.95 (dd, 1H, JZ10.6,
1.2 Hz); 5.25 (dd, 1H, JZ17.2, 1.2 Hz); 5.87 (dd, 1H, JZ
10.6, 17.2 Hz); 7.30–7.60 (br s, 1H, OH: exchanges with
D2O); 7.35–7.41 (m, 3H, aromatic protons); 7.54–7.59 (m,
2H, aromatic protons). 13C NMR (75 MHz, CDCl3, d): 28.1,
39.0, 73.9, 112.1, 127.0, 128.8, 129.7, 136.9, 144.6, 157.9.
GC–MS (70 eV) m/z (rel int.): 205 (MC, 4), 189 (16), 188
(100), 171 (20), 170 (16), 169 (10), 160 (20), 148 (39), 146
(20), 144 (25), 135 (15), 134 (25), 130 (57), 129 (17), 117
(23), 115 (14), 106 (19), 104 (38), 103 (38), 91 (20), 78 (10),
77 (60), 51 (17), 43 (48). Anal. Calcd for C12H15NO2: C,
70.22; H, 7.37; N, 6.82. Found: C, 70.21; H, 7.35; N, 6.80.
2.6.1. 5-(2-Ethoxyethyl)-3-phenylisoxazole (11b). Yield
24% (211 mg). Oil. FT-IR (KBr): 3029, 2925, 1603, 1580,
1481, 1443, 1407, 1113, 770, 694 cmK1 1H NMR
.
(200 MHz, CDCl3, d): 1.20 (t, 3H, JZ7.0 Hz); 3.07 (t,
2H, JZ6.5 Hz); 3.53 (q, 2H, JZ7.0 Hz); 3.77 (t, 2H, JZ
6.5 Hz); 6.39 (s, 1H); 7.41–7.46 (m, 3H, aromatic protons);
7.76–7.81 (m, 2H, aromatic protons). 13C NMR (75 MHz,
CDCl3, d): 15.3, 28.0, 66.7, 67.7, 100.1, 127.0, 129.1, 130.0,
162.7, 171.5. GC–MS (70 eV) m/z (rel int.): 217 (MC, 66),
187 (15), 159 (11), 144 (21), 130 (18), 117 (11), 116 (10),
104 (15), 103 (12), 89 (10), 77 (35), 59 (100), 51 (14). Anal.
Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C,
71.85; H, 6.95; N, 6.42.
2.9. Reaction of 5-hydroxy-3-phenyl-5-vinyl-2-isoxazo-
line with n-BuLi
A 2.1 M solution of n-BuLi in hexane (3.16 mL,
6.613 mmol) was added to a solution of 5-hydroxy-3-
phenyl-5-vinyl-2-isoxazoline (7) (500 mg, 2.645 mmol) in
THF (26 mL) kept at 0 8C under nitrogen, using a nitrogen-
flushed two necked flask equipped with a magnetic stirrer
and a nitrogen inlet. The obtained red reaction mixture was
stirred for 1 h at 0 8C before to add aq NH4Cl. The two
phases were separated and the aqueous layer was extracted
three times with EtOAc. The combined organic extracts
were dried over anhydrous Na2SO4 and then the solvent was
evaporated under reduced pressure. Column chromato-
graphy (silica gel, petroleum ether/ethyl acetateZ7:3) of
the residue afforded 5-hexyl-5-hydroxy-3-phenylisoxazo-
line (18b) in 64% yield and 3-hydroxy-1-phenyl-3-
vinylheptan-1-one oxime (17b) in 29% yield (Scheme 6
and Table 1).
2.7. Reaction of 5-hydroxy-3-phenyl-5-vinyl-2-isoxazo-
line with Na2CO3 in i-PrOH/H2O
A solution of Na2CO3 (482 mg, 4.55 mmol) in water
(20 mL) was added to 5-hydroxy-3-phenyl-5-vinyl-2-iso-
xazoline (7) (430 mg, 2.27 mmol) in i-PrOH (20 mL)
contained in a round bottom flask equipped with a magnetic
stirrer. The reaction mixture was then refluxed for 2 h. The
i-PrOH was evaporated under reduced pressure and aqueous
layer was extracted three times with CH2Cl2. The combined
organic extracts were dried over anhydrous Na2SO4 and the
solvent was evaporated under reduced pressure. Column
chromatography (silica gel, petroleum ether/ethyl acetateZ
7:3) of the residue afforded 3-phenyl-5-vinylisoxazole (9) in
48% yield (Table 1).
2.9.1. 5-Hexyl-5-hydroxy-3-phenylisoxazoline (18b).
Yield 64% (418 mg). Colourless oil. FT-IR (neat): 3600–
3200, 3061, 2955, 2928, 2859, 1599, 1568, 1498, 1466,
1
1447, 1361, 1234, 1075, 919, 759, 692 cmK1. H NMR
(CDCl3, d): 0.89 (t, 3H, JZ6.4 Hz); 1.30–1.59 (m, 8H);

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L. Di Nunno et al. / Tetrahedron 61 (2005) 11270–11278
1.90–2.03 (m, 2H); 2.85–3.00 (br s, 1H, OH: exchanges with
D2O); 3.27 (s, 2H); 7.36–7.45 (m, 3H, aromatic protons);
7.62–7.68 (m, 2H, aromatic protons). 13C NMR (75 MHz,
CDCl3, d): 14.3, 22.7, 24.9, 29.5, 31.9, 38.6, 44.7, 109.1,
126.9, 128.9, 129.8, 130.5, 157.6. GC–MS (70 eV) m/z (rel
int.): 247 (MC, 14), 231 (11), 230 (56), 229 (29), 186 (10),
172 (23), 162 (10), 159 (21), 146 (15), 144 (39), 135 (68),
134 (22), 118 (18), 117 (100), 113 (46), 104 (12), 103 (25),
85 (24), 77 (55), 57 (14), 55 (14), 51 (13), 43 (63), 41 (20).
Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66.
Found: C, 72.85; H, 8.55; N, 5.62.
2.13–2.21 (m, 2H); 2.70–2.85 (m, 2H); 2.94–3.04 (m, 1H);
6.28 (s, 1H); 6.34 (s, 1H); 7.40–7.48 (m, 6H, aromatic
protons); 7.73–7.81 (m, 4H, aromatic protons). 13C NMR
(75 MHz, CDCl3, d): 14.2, 22.7, 24.9, 27.0, 31.8, 32.1, 34.2,
38.0, 99.4, 99.5, 127.0, 129.1, 129.4, 130.1, 162.6, 173.1,
176.1. GC–MS (70 eV) m/z (rel int.): 400 (MC, 14), 330 (4),
243 (18), 242 (100), 240 (12), 229 (15), 200 (6), 186 (8), 173
(9), 172 (49), 159 (30), 144 (34), 130 (6), 117 (32), 116 (11),
104 (8), 89 (7), 77 (27), 55 (12). Anal. Calcd for
C26H28N2O2: C, 77.97; H, 7.05; N, 6.99. Found: C, 78.00;
H, 7.02; N, 7.01.
2.9.2. 3-Hydroxy-1-phenyl-3-vinylheptan-1-one oxime
(17b). It was not isolated as a pure compound, but mixed
with 5-hexyl-5-hydroxy-3-phenylisoxazoline (18b) in the
ratio 65:35. 29% yield (189 mg). Yellow oil. 1H NMR
(CDCl3, d): 0.81 (t, 3H, JZ6.5 Hz); 1.10–1.63 (m, 6H); 3.00–
3.30 (br s, 1H, OH: exchanges with D2O); 3.08 (d, 1H, JZ
13.4 Hz); 3.22 (d, 1H, JZ13.4 Hz); 4.96 (dd, 1H, JZ10.7,
1.5 Hz);5.22(dd,1H, JZ17.1, 1.5 Hz);5.71(dd,1H, JZ10.7,
17.1 Hz); 7.30–7.45 (m, 3H, aromatic protons); 7.48–7.60 (m,
2H, aromatic protons); 8.60–9.30 (br s, 1H, OH: exchanges
with D2O). 13C NMR (75 MHz, CDCl3, d): 14.3, 23.2, 25.9,
38.3, 41.9, 76.3, 113.0, 127.1, 128.7, 129.0, 129.6, 137.0,
143.1, 158.4. LC–MS (ESIC) m/z: 270.1 (45) [MCNa]C.
2.11. Reaction of 5-hydroxy-3-phenyl-5-vinyl-2-isoxazo-
line with m-CPBA
m-CPBA (70%, 1.546 g, 6.275 mmol) was added to a
solution of 5-hydroxy-3-phenyl-5-vinyl-2-isoxazoline (7)
(475 mg, 2.51 mmol) in anhydrous CH2Cl2 (24 mL)
contained in a round bottom flask equipped with a magnetic
stirrer. The mixture was stirred for 24 h at room temperature
before to add 10% aq K2CO3. The two phases were
separated, and the aqueous layer was extracted three times
with CH2Cl2. The combined organic extracts were dried
over anhydrous Na2SO4 and then, the solvent was
evaporated under reduced pressure. Column chromato-
graphy (silica gel, petroleum ether/ethyl acetateZ8:2) of
the yellow solid crude afforded 73% yield of 5-hydroxy-5-
(oxiran-2-yl)-3-phenyl-2-isoxazoline (21), 10% yield of
3-phenyl-5-vinylisoxazole (9) and 10% yield of 5-(oxiran-
2-yl)-3-phenyl-isoxazole (22).
2.10. Reaction of 3-phenyl-5-vinylisoxazole with n-BuLi
A 2.10 M solution of n-butyllithium in hexane (1.873 mL,
3.933 mmol) was added to 3-phenyl-5-vinylisoxazole
(0.269 g, 1.573 mmol) in THF (13 mL) kept at K78 8C
under nitrogen, using a nitrogen-flushed two necked flask
equipped with a magnetic stirrer and a nitrogen inlet. The
obtained red reaction mixture was stirred for 2 h at K78 8C
before to add aq NH4Cl. The two phases were separated and
aqueous layer was extracted three times with ethyl acetate.
The combined organic extracts were dried over anhydrous
Na2SO4 and then the solvent was evaporated under reduced
pressure. Column chromatography (silica gel, petroleum
ether/ethyl acetateZ8:2) of the residue afforded 3-phenyl-5-
(3-(3-phenylisoxazol-5-yl)octyl)isoxazole (20) in 89% yield
and 5-hexyl-3-phenylisoxazole (19) in 10% yield.
2.11.1. 5-Hydroxy-5-(oxiran-2-yl)-3-phenyl-2-isoxazo-
line (21). Diastereoisomeric ratioZ64:36 (determined by
1H NMR). 73% yield (375 mg). Mp 58–61 8C, white solid.
FT-IR (KBr): 3600–3200, 3062, 2925, 2852, 1601, 1569,
1527, 1498, 1447, 1417, 1362, 1264, 1218, 1093, 906, 858,
761, 691 cmK1. 1H NMR (CDCl3, d): 2.83 (dd, 1H, JZ2.7,
5.1 Hz, oxiranyl proton of the major diastereoisomer); 2.88
(dd, 1H, JZ4.0, 5.1 Hz, oxiranyl proton of the major
diastereoisomer); 2.90–2.95 (m, 2H, oxiranyl protons of the
minor diastereoisomer); 3.22–3.48 (m, 6H, isoxazoline ring
CH2 and oxiranyl CH of both diastereoisomers); 3.56–3.74
(br s, 2H, OH: exchange with D2O, 1H for each
diastereoisomer); 7.35–7.44 (m, 6H, aromatic protons of
both diastereoisomers), 7.62–7.68 (m, 4H, aromatic protons
of both diastereoisomers). 13C NMR (75 MHz, CDCl3, d):
43.0 (minor diastereoisomer), 43.8 (major diastereoisomer),
44.3 (major diastereoisomer), 45.2 (minor diastereoisomer),
53.0 (major diastereoisomer), 53.1 (minor diastereoisomer),
104.9 (major diastereoisomer), 106.7 (minor diastereo-
isomer), 127.0, 129.0, 129.1, 130.7, 157.1 (major diastereo-
isomer), 157.7 (minor diastereoisomer). GC–MS (70 eV)
m/z (rel int.): 205 (MC, 46), 188 (11), 162 (49), 144 (14),
134 (12), 120 (29), 118 (13), 117 (70), 104 (27), 103 (66), 91
(20), 78 (11), 77 (100), 76 (13), 63 (8), 51 (25), 43 (16).
Anal. Calcd for C11H11NO3: C, 64.38; H, 5.40; N, 6.83.
Found: C, 64.40; H, 5.44; N, 6.82.
2.10.1. 5-Hexyl-3-phenylisoxazole (19). Yield 10%
(36 mg). Oil. FT-IR (neat): 3127, 3053, 2930, 2859, 1602,
1580, 1471, 1443, 1408, 1378, 1079, 950, 916, 767,
1
693 cmK1. H NMR (CDCl3, d): 0.90 (t, 3H, JZ7.0 Hz);
1.24–1.45 (m, 6H); 1.74 (quintet, 2H, JZ7.3 Hz); 2.79 (t,
2H, JZ7.3 Hz); 6.28 (s, 1H); 7.40–7.47 (m, 3H, aromatic
protons); 7.76–7.82 (m, 2H, aromatic protons). 13C NMR
(75 MHz, CDCl3, d): 14.3, 22.7, 27.0, 27.7, 29.0, 31.6, 99.0,
127.0, 129.1, 129.7, 130.0, 162.5, 174.5. GC–MS (70 eV) m/z
(rel int.): 229 (MC, 62), 200 (6), 186 (23), 173 (10), 172 (48),
159 (42), 158 (13), 145 (13), 144 (74), 130 (9), 118 (14), 117
(100), 116 (16), 104 (10), 89 (12), 77 (39), 68 (9), 55 (9), 51
(10), 43 (11), 41 (12). Anal. Calcd for C15H19NO: C, 78.56;
H, 8.35; N, 6.11. Found: C, 78.55; H, 8.32; N, 6.09.
2.10.2. 3-Phenyl-5-(3-(3-phenylisoxazol-5-yl)octyl)isoxa-
zole (20). Yield 89% (280 mg). Oil. FT-IR (KBr): 3113,
3030, 2925, 2856, 1599, 1577, 1470, 1443, 1409, 1380,
1081, 951, 907, 771, 692 cmK1. 1H NMR (CDCl3, d): 0.86
(t, 3H, JZ6.2 Hz); 1.23–1.38 (m, 6H); 1.67–1.79 (m, 2H);
2.12. Reaction of 3-phenyl-5-vinylisoxazole (9) with
m-CPBA
m-CPBA (70%, 0.995 g, 4.035 mmol) was added to a
solution of 3-phenyl-5-vinylisoxazole
9
(276 mg,

L. Di Nunno et al. / Tetrahedron 61 (2005) 11270–11278
11277
1.614 mmol) in anhydrous CH2Cl2 (20 mL) contained in a
round bottom flask equipped with a magnetic stirrer. The
reaction mixture was stirred for 24 h at room temperature
before to add 10% aq K2CO3. The two phases were
separated and the aqueous layer was extracted three times
with CH2Cl2. The combined organic extracts were dried
over anhydrous Na2SO4 and then the solvent was
evaporated under reduced pressure. The reaction was
quantitative. The 5-(oxiran-2-yl)-3-phenylisoxazole (22)
was obtained in 80% yield after crystallization (hexane).
other diastereoisomer), 107.9 (one diastereoisomer), 108.3
(the other diastereoisomer), 126.5, 126.68, 126.73, 128.7,
129.2, 129.3, 129.6, 130.3, 157.4 (one diastereoisomer),
157.5 (the other diastereoisomer), 157.6, 157.7. LC–MS
(ESIC) m/z: 331.2 (100) [MC Na]C. Anal. Calcd for
C18H16N2O3: C, 70.12; H, 5.23; N, 9.09. Found: C, 70.15;
H, 5.24; N, 9.01.
2.14. Reaction of 3-phenyl-5-vinylisoxazole with benzo-
nitrile oxide
2.12.1. 5-(Oxiran-2-yl)-3-phenyl-isoxazole (22). Yield
80% (241 mg). Mp 64–65 8C (hexane), white crystals.
FT-IR (KBr): 3114, 2918, 2850, 1616, 1582, 1475, 1446,
1408, 1361, 1293, 1242, 1186, 1140, 1003, 952, 923, 864,
A solution of benzonitrile oxide (1.683 mmol) in anhydrous
THF (10 mL) was dropwise added to a solution of 3-phenyl-
5-vinylisoxazole 9 (240 mg, 1.403 mmol) in anhydrous
THF (10 mL) contained in a round bottom flask equipped
with a magnetic stirrer. The reaction mixture was stirred for
3 h at room temperature before a satd aq NH4Cl was added.
The two phases were separated and the aqueous layer was
extracted three times with AcOEt. The combined organic
extracts were dried over anhydrous Na2SO4 and then the
solvent was evaporated under reduced pressure. Column
chromatography (silica gel, petroleum ether/ethyl acetateZ
8:2) of the residue afforded 3-phenyl-5-(3-phenyl-2-iso-
xazolin-5-yl)isoxazole (24) in 80% yield after crystal-
lization (EtOH).
1
834, 822, 767, 694 cmK1. H NMR (200 MHz, CDCl3, d):
3.20 (dd, 1H, JZ2.6, 5.5 Hz); 3.25 (dd, 1H, JZ3.8, 5.5 Hz);
4.05 (ddd, 1H, JZ0.3, 2.6, 3.8 Hz); 6.57 (d, 1H, JZ0.3 Hz);
7.41–7.49 (m, 3H, aromatic protons); 7.74–7.85 (m, 2H,
aromatic protons). 13C NMR (75 MHz, CDCl3, d): 45.1,
49.2, 100.8, 127.0, 128.8, 129.2, 130.4, 162.8, 169.3. GC–
MS (70 eV) m/z (rel int.): 187 (MC, 62), 171 (5), 158 (14),
145 (11), 144 (100), 130 (14), 128 (12), 127 (26), 126 (8),
116 (26), 103 (36), 89 (11), 77 (61), 63 (8), 51 (22). Anal.
Calcd for C11H9NO2: C, 70.58; H, 4.85; N, 7.48. Found: C,
70.60; H, 4.84; N, 7.46.
2.14.1. 3-Phenyl-5-(3-phenyl-2-isoxazolin-5-yl)isoxazole
(24). Yield 80% (325 mg). Mp 110–112 8C (lit.24 108–
109 8C), white crystals. FT-IR (KBr): 3122, 3049, 2979,
2915, 2894, 1614, 1473, 1446, 1406, 1362, 1164, 1084,
2.13. Reaction of 5-hydroxy-3-phenyl-5-vinyl-2-isoxazo-
line with benzonitrile oxide
1007, 921, 887, 757, 691 cmK1 1H NMR (200 MHz,
.
A solution of benzonitrile oxide (0.634 mmol) in anhydrous
THF (5 mL) was dropwise added to a solution of 5-hydroxy-
3-phenyl-5-vinyl-2-isoxazoline (7) (100 mg, 0.529 mmol)
in anhydrous THF (24 mL) contained in a round bottom
flask equipped with a magnetic stirrer. The reaction mixture
was stirred for 3 h at room temperature before to add satd aq
NH4Cl. The two phases were separated and the aqueous
layer was extracted three times with AcOEt. The combined
organic extracts were dried over anhydrous Na2SO4 and
then the solvent was evaporated under reduced pressure.
Column chromatography (silica gel, petroleum ether/ethyl
acetateZ8:2) of the residue afforded 5-hydroxy-3-phenyl-5-
(3-phenyl-2-isoxazolin-5-yl)-2-isoxazoline (23) in 70%
yield.
CDCl3, d): 3.67 (dd, 1H, JZ7.0, 16.7 Hz); 3.80 (dd, 1H, JZ
10.8, 16.7 Hz); 5.88 (ddd, 1H, JZ0.6, 7.0, 10.8 Hz); 6.68 (d,
1H, JZ0.6 Hz); 7.40–7.48 (m, 6H, aromatic protons); 7.66–
7.72 (m, 2H, aromatic protons); 7.75–7.81 (m, 2H, aromatic
protons). 13C NMR (75 MHz, CDCl3, d): 40.4, 74.5, 100.7,
127.1, 127.2, 128.8, 129.1, 129.2, 130.4, 130.9, 156.6,
162.8, 170.9. GC–MS (70 eV) m/z (rel int.): 290 (MC, 100),
260 (17), 171 (25), 145 (10), 144 (78), 143 (20), 117 (12),
116 (12), 103 (7), 89 (9), 77 (44), 63 (5), 51 (14). Anal.
Calcd for C18H14N2O2: C, 74.47; H, 4.86; N, 9.65. Found:
C, 74.50; H, 4.85; N, 9.62.
Acknowledgements
2.13.1. 5-Hydroxy-3-phenyl-5-(3-phenyl-2-isoxazolin-5-
yl)-2-isoxazoline (23). Yield 70% (114 mg, mixture of the
two diastereoisomers, drZ1:1). Mp 194–197 8C (EtOH),
white crystals. FT-IR (KBr): 3574, 3426 (strong broad
band), 3050, 2987, 2925, 2853, 1598, 1569, 1497, 1447,
1360, 1253, 1219, 1103, 891, 811, 755, 688 cmK1. 1H NMR
(acetone-d6, d): 2.92 (s, 1H, OH: exchanges with D2O,
one diastereoisomer); 3.35 (dd, 1H, JZ6.7, 17.8 Hz, one
diastereoisomer); 3.50–3.73 (m, 7H, three protons of one
diastereoisomer and four of the other diastereoisomer);
5.02–5.09 (m, 2H, one proton for each diastereoisomer);
6.30 (d, 1H, JZ8.8 Hz, OH: exchanges with D2O, the other
diastereoisomer); 7.40–7.48 (m, 12H, aromatic protons,
both diastereoisomers); 7.68–7.77 (m, 8H, aromatic protons,
both diastereoisomers). 13C NMR (75 MHz, CD3OD, d):
36.1 (one diastereoisomer), 36.9 (the other diastereo-
isomer), 41.3 (one diastereoisomer), 42.4 (the other
diastereoisomer), 82.07 (one diastereoisomer), 82.13 (the
Work carried out under the framework of the National
Projects ‘Stereoselezione in Sintesi Organica. Metodologie
ed Applicazioni’ supported by the Ministero dell’Istruzione,
`
dell’Universita e della Ricerca (MIUR, Rome), ‘Progetto
Strategico BS2—PREVENZIONE, DIAGNOSTICA PRE-
COCE E CONTROLLO DELLA MALATTIA NEO-
PLASTICA’ supported by the Ministero della Salute
(MinSan, Rome), and by the University of Bari and Istituto
di Chimica dei Composti OrganoMetallici (ICCOM-CNR,
Bari).
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