Revisiting the addition of nitriloxides on protoanemonin. A new access to (2E)-3-(3'-arylisoxazol-5'-yl)propenoic acids

Article abstract of DOI:10.1039/b001481h

Some 4-substituted arylnitriloxides undergo 1,3-dipolar cycloadditions with 5-methylene(5H)furan-2-one (protoanemonin) with formation of spiroisoxazolines. These spiroadducts can be opened to the corresponding (2E)3-(3'-arylisoxazol-5'-yl)propenoic acids 5 and 3-aryl-5[4'-(3'-aryl- 4',5'-dihydroisoxazolinyl)]isoxazole 6 by various ways, including acidic and basic treatments, as well as electrooxidation. In the latter case, the electron transfer occurs on the 4,5-dihydroisoxazolic ring and is followed by an internal dissociative electron transfer leading to the opened products.

Full text of DOI:10.1039/b001481h

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Revisiting the addition of nitriloxides on protoanemonin. A new access
to (2E)-3-(3º-arylisoxazol-5º-yl)propenoic acids¤
Christophe Roussel,a Rachid Fihi,a Kabula Ciamala,*a Pierre Audebertb and Joel Vebrela
a L aboratoire de Chimie et Electrochimie Moleculaire, Universite de Franche Comte, 16 route de
Gray, F-25030 Besancon cedex, France. E-mail: Christophe.Roussel=univ-fcomte.fr
b L aboratoire de Photophysique et Photochimie Supramoleculaire et Macromoleculaire, Ecole
Normale Superieure de Cachan, 71 Av. du Pdt W ilson, F-94235 Cachan cedex, France.
E-mail: audebert=ppsm.ens-cachan.fr
Received (in Montpellier, France) 21st February 2000, Accepted 5th April 2000
Published on the Web 22nd May 2000
Some 4-substituted arylnitriloxides undergo 1,3-dipolar cycloadditions with 5-methylene(5H)furan-2-one
(protoanemonin) with formation of spiroisoxazolines. These spiroadducts can be opened to the corresponding (2E)-
3-(3@-arylisoxazol-5@-yl)propenoic acids 5 and 3-aryl-5[4@-(3@-aryl-4@,5@-dihydroisoxazolinyl)]isoxazole 6 by various
ways, including acidic and basic treatments, as well as electrooxidation. In the latter case, the electron transfer
occurs on the 4,5-dihydroisoxazolic ring and is followed by an internal dissociative electron transfer leading to the
opened products.
Reinvestigation de lÏaddition des nitriloxydes sur la protoanemonine. Nouvelle voie dÏacces aux acides (2E)-3-(3º-
arylisoxazol-5º-yl)propeno•que. Nous avons fait reagir quelques arylnitriloxydes substitues en position 4 sur le cycle
aromatique avec la 5-methylene(5H)furan-2-one (protoanemonine) via une reaction de cycloaddition [3 ] 2]. La
reaction conduit a lÏobtention dÏun melange de mono et bis-adduits. Ces spiroadduits peuvent se rearranger en
acide (2E)-3-(3@-arylisoxazol-5@-yl)prop-2-eno•que 5 et en 3-aryl-5[4@-(3@-aryl-4@,5@-dihydroisoxazolinyl)]isoxazole 6
en milieu acide, basique et par electrooxydation. Dans ce dernier cas, lÏoxydation intervient sur le cycle
isoxazolinique suivi dÏun transfert electronique dissociatif conduisant au produit dÏouverture.
In a previous article1 we showed that the cycloaddition of
methylene-c-butyrolactones with arylnitriloxides is regio-
speciÐc. It usually leads to monoadducts, whatever the tem-
perature. However, in the case of 5-methylene(5H)furan-2-one
1 (usually called protoanemonin), when this reaction is run in
reÑuxing toluene, an unexpected rearrangment compound is
obtained. Since protoanemonin has two reactive sites instead
of only one as in the other compounds studied, there was a
strong presumption that an intermediate bis-adduct could
have been generated in the course of the reaction. Therefore,
we decided to search for the reaction conditions that would
allow us to isolate this supposed bis-adduct; we succeeded in
Ðnding the conditions that allow either monoadducts (3a–d)
or bis-adducts (4a–c) to be isolated. In addition, we submitted
the bis-adducts to acidic or basic catalytic reaction conditions
(Scheme 1).
Indeed, the expected, previously observed rearrangement
leading
to
3-aryl-5[4@-(3@-aryl-4@,5@-dihydroisoxazolinyl)]-
isoxazole (6a–c) was again observed, thus conÐrming our
initial hypothesis. When submitted to the same reaction con-
ditions, the spiroheterocycles (3a–d) (the monoadducts of the
previous reaction) react giving (2E)-3-(3@-arylisoxazol-5@-yl)
propenoic acids (5a-d). It should be remarked that the
homologues of these acids, bearing a halogen or hydroxyl
substituent on the 3@ position, are known as synthetic inter-
mediates in the synthesis of natural products belonging to the
ibotenic acid [(R,S)-a-amino-3-hydroxyisoxazole-5-acetic acid]
group. Up to now, they were only known as reactional
¤ Electronic supplementary information (ESI) available: NOESY 2D
NMR spectra of the bis-adduct 4b. See http://www.rsc.org/suppdata/
nj/b0/b001481h/
Scheme 1
DOI: 10.1039/b001481h
New J. Chem., 2000, 24, 471È476
471
This journal is ( The Royal Society of Chemistry and the Centre National de la Recherche ScientiÐque 2000

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bioproducts,2h4 while we propose here a three-step total syn-
thesis.
strongly deshielded (D5.65 ppm vs. TMS), showing that it is
vicinal to an oxygen. Therefore, the protons 4@-H are close to
the most deshielded protons of the structure and the bis-
All the compounds issued from the cycloaddition reactions
were submitted to electrochemical oxidation on a platinum
electrode. The monoadducts react as previously determined,5
with the intervention of a catalytic mechanism, leading to the
(2E)-3-(3@-arylisoxazol-5@-yl)propenoic acids 5a–d. In contrast,
the bis-adducts are extremely stable towards oxidation,
remaining unchanged even when submitted to potentials of up
to 3 V vs. SCE.
adducts have the structure 4 .
1
The regiochemistry thus established has previously been
conÐrmed by an X-ray study1 of the rearrangement product
6b issued from the bis-adducts 4b (Scheme 2).
Chemical opening of the adducts
Bis-adducts. The bis-adducts were submitted to both acidic
and basic treatments (triÑuoroacetic acid at reÑux and eth-
anolic NaOH at room temperature, respectively), and lead to
compounds that are similar to the previously identiÐed com-
pounds in another analogous series of adducts.1 However,
while the acidic treatment directly leads to compounds 6a–c,
the basic treatment Ðrst gives an inseparable mixture of two
acids, which is attested by the existence in the 1H NMR spec-
trum of two di†erent AB systems, as well as several exchange-
able protons. However, upon neutralization and further
reÑuxing for 24 h, the expected 6a–c products are formed
quantitatively. For each treatment, we propose the mecha-
nisms shown on Scheme 3. In addition, we have veriÐed that
compounds 4a–c are stable upon 24 h in reÑuxing toluene, but
also yield the expected rearrangement products 6a–c upon
treatment with a catalytic amount of triethylamine. This
shows that the base-induced opening is clearly more efficient
than the acid-induced one.
Results and discussion
Cycloadditions
The tuning of the experimental conditions of the cyclo-
addition of protoanemonin 1 with arylnitriloxides (generated
in situ from the reaction of 2a–d with triethylamine) allow the
monoadducts, the bis-adducts or a mixture to be produced. In
fact, when the reaction is run at room temperature in diethyl
ether under classical conditions, with a 1 : 1 stoichiometry,
only the monoadducts 3a–d are obtained (Scheme 1).
However, when the reaction is run similarly, but under nitro-
gen and in the absence of UV light, a mixture of mono and
bis-adducts is obtained, the amount of which depends upon
the nature of the substituent on the 4 position of the arylnitril-
oxide (see experimental). It should in addition be recalled that,
from the examination of the NMR spectra of the crude reac-
tion products, about 10% of anemonin (dimeric form of
protoanemonin) is formed, as previously observed by E.
Shaw.6 The introduction of a catalytic amount of a radical
inhibitor such as hydroquinone, nitrobenzene or p-
nitrophenol leads to the sole formation of bis-adducts 4a–c,
whatever the stoichiometry of the reactants, along with the
absence of anemonin.
Monoadducts. The monoadducts 3a–d rearrange into (2E)-3-
(3@-arylisoxazol-5@-yl)propenoic acids 5a–d (Scheme 4) upon
treatment with HCl in acetonitrile or ethanolic NaOH under
much gentler conditions (e.g., 15 min at room temperature in
acidic medium). In addition to the IR data, the structure of
the rearrangement products is conÐrmed by the presence of
two ethylenic protons with a coupling constant J \ 12.8 Hz,
as well as a D O exchangeable proton, while the mass
2
In all cases, the regiochemistry of the cycloaddition is
unique, thus attesting to the regiospeciÐcity of both mecha-
nisms. The regiochemistry of the adducts can be determined
by the examination of the 13C NMR displacements of the spi-
ranic junction carbon. In the case of the monoadducts 3a–d,
the observed value of 112.5 ppm vs. TMS is in favor of the
structure 3 shown on Scheme 1. In the case of the bis-adducts
4a–c, a straightforward unambiguous determination is not
possible, as the observed values of 113È115 ppm are in
accordance with both structures 4 and 4 (Scheme 2).
remained unchanged throughout the reaction (e.g., m/z \ 215
for 5a).
Electrochemical opening of the adducts
General features. We have submitted the adducts to electro-
chemical oxidation. In our previous report on related benzo-
condensed adducts, we had found that an original oxidation
took place, leading to the normal open products, the 2-(3-
arylisoxazol-5-yl)benzoic acids, through an uncommon elec-
trocatalytic mechanism.5 However, in the present case, the
behavior of the two types of adducts obtained from protoane-
monin has been found to di†er. The bis-adducts are resistant
to oxidation up to 3 V. Despite an oxidation peak discernable
in the 2.5È3 V region, using low scan rate cyclic voltammetry,
the electrolysis is not possible due to the too high residual
solvent oxidation at these elevated potentials, even in
dichloromethane. In contrast, the monoadducts can be oxi-
dized around 2 V in dichloromethane or acetonitrile.
1
2
Therefore, a NOESY 2D NMR study was realized, which
shows that there is a correlation between the protons 4@-H and
6a-H in 4 or between 4@-H and 3a-H in 4 , therefore close
1
2
spatially; on the other hand the proton correlated with 4@-H is
Oxidation of the monoadducts. Fig. 1 displays the cyclic
voltammograms for the oxidation of the monoadducts 3a–d. It
is clear that, with the exception of 3d, a single well deÐned
oxidation peak is obtained. Although the oxidation of only
three di†erent substituted adducts was investigated, the poten-
tials (see Table 1) correlate well with the Hammett coefficient
p` of the substituents on the phenyl ring (Fig. 2). This would
suggest a Ðrst oxidation process involving electron abstraction
from the 4,5-dihydroisoxazolic ring and not from the lactone,
while this was not obvious in the case of the benzocondensed
adducts (the broadness of the catalytic wave impeded any
precise potential correlation). Comparison of the peak cur-
rents with a ferrocene standard allows us to determine that
the peaks are monoelectronic.
This is in addition corroborated by the fact that one
Faraday per mole is exchanged during the electrolyses. It
Scheme 2
472
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Scheme 3
should be emphasized that, despite the opened products
having the same oxidation state as the monoadducts, the elec-
tron exchange results in the production of one proton fol-
lowed by a solvent oxidation process. The compounds issued
from the electrochemical oxidation are the classic ring-
opening products, and in all cases very good yields of isolated
products are obtained (see Experimental). Coulombic yields
are also very fair, on the basis of one Faraday per mole.
Only the adduct 3d exhibits the catalytic oxidation pre-
viously observed with the benzocondensed adducts. This is
probably due to the high electron-attracting character of the
Fig. 1 Electrochemical oxidation of the spiroadducts 3aÈd in
CH CN ] 0.1 M TEAP performed on a 1 mm diameter Pt electrode,
3
scan rate 0.05 V s~1, c \ 5 mM.
Table 1 Electrochemical data for spiroadduct 3
Product
E a/V
E a/V
E a/V
tb/min
p
v
w
3a
3b
3c
3d
2.24
2.08
1.83
2.51c
2.10
2.00
1.70
2.00
10
10
10
10
1.80È2.35
a E : peak potential; E : catalytic wave potential; E : working elec-
p
v
w
trode potential during the electrolysis; all potentials are vs. SCE.
b Electrolysis time. c Peak potential of the product 5d.
Table 2 Electrochemical data for ring-opening product 5
Product
E a/V
p
5a
5b
5c
5d
2.52
2.24
1.90
2.51
a E : peak potential vs. SCE.
p
Scheme 4
New J. Chem., 2000, 24, 471È476
473

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To summarize, in light of the previous discussion, we
propose the mechanism shown in Scheme 5 for the oxidative
one-electron opening of the monoadducts 3a–c.
Conclusion
We have studied the cycloaddition reaction of several arylni-
trile oxides with protoanemonin. We have shown that depend-
ing on the reaction conditions, either the monoaddition or the
bis-addition products can be obtained selectively. The ring-
opening of the adducts has been examined and can occur, in
basic and acidic medium, or through an oxidative process in
the case of the monoadducts. In this latter case, the oxidation
process take place by a one-electron transfer, contrary to the
case of the previously examined benzocondensed adducts.
Fig. 2 Correlation between the oxidation peak and the Hammett
coefficient p` for products 3aÈc.
nitro group, which impedes the oxidation process on the iso-
xazoline, therefore oxidation is more liable to occur in this
case on the lactone ring. In order to conÐrm this analysis, we
have examined the oxidation of compounds possessing the
same lactonic structure as the adducts, namely c-
butyrolactone, 2(5H)furanone and 1(3H)isobenzofuranone.
Only the phthalide is oxidized through the catalytic process
previously observed,5 while the other lactones are not oxidiz-
able in the accessible potential range of the solvent (up to 3
V). This conÐrms that the monoadduct oxidation process
occurs on the unsaturated 4,5-dihydroisoxazolic ring, and
involves certainly the unsaturated C2N bond. However, the
unreactivity of the bis-adducts towards electrochemical oxida-
tion remains surprising, given that they also contain the same
4,5-dihydroisoxazolic rings, although somewhat deactivated.
From the fact that the bis-adducts are not oxidizable, it is
clear that the double bond coming from the precursor proto-
anemonin ring plays a crucial role in the oxidation process of
the monoadducts (certainly of the same kind as that pre-
viously played by the benzylic ring in the case of the benzo-
condensed compounds5). However, from the dependence of
the peak potentials with the Hammett coefficients, we know
that the initial electron transfer should take place on the 4,5-
dihydroisoxazolic ring (though this is not completely clear in
the case of the weakly reactive 3d adduct). This apparent con-
tradiction can only be solved by the occurrence of an intra-
molecular dissociative electron transfer, shown on Scheme 5.
The intramolecular electron transfer should be strongly favored
by the downhill process of the opening reaction, enhanced by
the stabilization of the positive charge by the double bond in
the opened cation radical. (One should remark that in the
present case, contrary to the benzocondensed adducts, no
catalytic mechanism takes place; this is probably due to the
inability of the radical produced to reoxidize the substrate;
this is not unexpected in regard to the completely conjugated
character of this isoxazoloallylic radical.) This phenomenon
was previously observed in reduction.7h10
Experimental
Materials and methods
The starting oleÐn 1 was synthesized according to the liter-
ature procedure11 (CS was replaced by Et O). The arylnitril-
2
2
oxides were prepared in situ by dehydrohalogenation of the
corresponding hydroxyamoyl chlorides 2aÈd according to ref.
12È16. Reactions were carried out under an atmosphere of dry
N
using a standard Schlenk tube protected from UV. Sol-
2
vents were puriÐed by standard methods and freshly distilled
under nitrogen.
Melting points were obtained on an Electrothermal IA 9200
and are not corrected. IR spectra (KBr) were recorded on a
BIO-RAD FTS-7 spectrometer. 1H, 13C and NOESY NMR
spectra were recorded on a Bruker-Spectrospin AC 200
spectrometer operating at 200 MHz for 1H, 50 MHz for 13C.
Chemical shifts were measured relative to TMS in CDCl or
3
[D ]acetone as solvent. Analytical data were obtained by the
6
CNRS (Vernaison, France) and were satisfactory (C, H, N
within ^0.30% from theoretical). Mass spectra were recorded
on a NERMAG R 1010 H apparatus under electronic impact
at 70 eV. Yields are given for isolated products.
Electrochemical setup
Analytical experiments were performed in
a
three-
compartment cell Ðtted with a saturated calomel reference
(SCE), a glassy carbon electrode (diameter 3 mm) or platinum
electrode (diameter 1 or 0.5 mm) and a platinum counter elec-
trode. The electrochemical apparatus was a home-made
potentiostat17 (equipped with an ohmic drop compensation
system) Ðtted with a PAR 173 Universal programmer, a
Nicolet digital oscilloscope and a Sefram 164 plotter. The
solvent was spectroscopic grade acetonitrile [distilled over
CaCl and stored on 3 A molecular sieves with 0.1 M tetra-
2
Scheme 5
474
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ethylamonium perchlorate (Fluka puriss, recrystallized once
from acetonitrileÈdiethyl ether)] as supporting electrolyte.
Concentration of product 3 or 4 was usually 1 or 5 ] 10~3 M
and the cell was Ñushed with argon throughout the experi-
ment. Ohmic compensation was used when necessary (i.e., for
scan rates over 1 V s~1).
Electrosyntheses were performed in a two-compartment cell
Ðtted with a SCE as reference electrode, a platinum work elec-
trode (diameter 15 mm) and platinum wire counter electrode.
The electrochemical apparatus was a radiometer PGP 201
potentiostat.
7.80 (d, J \ 8.9 Hz, 2H, arom H); 8.25 (d, J \ 8.9 Hz, 2H,
arom H). 13C NMR (CDCl , d): 42.5, 112.7, 124.1È148.3,
3
148.3, 160.6, 168.9.
4a: Yield 0.43 g (26%) by method A, 1 g (60%) by method
B, m.p. 220È222 ¡C (acetone), colorless solid, anal. calcd. for
C
H
N O : C, 68.26; H, 4.22; N, 8.38. Found C, 68.38; H,
19 14
2 4
4.26; N, 8.41. IR (KBr): l 1790 1620, 1600 cm~1. 1H NMR
(CDCl , d): 3.50È4.20 (AB system, J \ 18.5 Hz, 2H, 4@-H);
3
4.95 (d, J \ 9.0 Hz, 1H, 3a-H); 5.65 (d, J \ 9.0 Hz, 1H, 6a-H);
7.35È8.05 (m, 10H, arom H). 13C NMR (CDCl , d): 41.8, 55.0,
3
85.7, 115.5, 126.9È131.1, 153.2, 158.3, 167.5. HRMS m/z: 334
(100%).
Synthesis of compounds 3a–d and 4a–c
4b: Yield 0.64 g (35%) by method A, 1.25 g (69%) by
method B, m.p. 216È218 ¡C (acetone), colorless solid, anal.
Method A. Mixture of 2,5-dihydro-3º-arylspiroisoxazolino-
calcd. for C
H
N O : C, 69.62; H, 5.01; N, 7.73. Found C,
21 18
2 4
[5º,5]furan-2-one
3
and
3,3º-diaryl-3a,6a-dihydro-4-
69.53; H, 4.91; N, 7.69. IR (KBr): l 1785, 1630, 1615 cm~1. 1H
oxospiro[isoxazolino-5º,6-isoxazolo[3,4-c]furanone] 4. To a
magnetically stirred solution of protoanemonin 1 (0.48 g, 5
NMR (CDCl , d): 2.40 (s, 6H, 2 CH ); 3.40È4.20 (AB system,
3
3
J \ 18.5 Hz, 2H, 4@-H); 4.90 (d, J \ 8.9 Hz, 1H, 3a-H); 5.60 (d,
J \ 8.9 Hz, 1H, 6a-H); 7.10È8.00 (m, 8H, arom H). 13C NMR
mmol) in dry Et O (20 mL) was added the appropriate pre-
2
cursor 2 (7 mmol) and the resulting mixture was stirred at 0 ¡C
(CDCl , d): 21.3, 41.9, 55.0, 85.5, 115.4, 126.9È141.6, 153.1,
3
under nitrogen for 15 min. Et N (1 mL) was then added and
158.2, 167.6.
3
the mixture stirred for 24 h at room temperature. The solvent
4c: Yield 0.83 g (42%) by method A, 1.45 g (74%) by
method B, m.p. 223È224 ¡C (acetone), white solid, anal. calcd.
was evaporated under reduced pressure, the residue was dis-
solved in CH Cl , and the resulting solution was washed with
for C
H
N O : C, 63.95; H, 4.60; N, 7.11. Found C, 63.67;
2
2
21 18
2
6
water (2 ] 100 mL). The organic layer was dried (Na SO )
H, 4.72; N, 6.79. IR (KBr): l 1790, 1630, 1605 cm~1. 1H NMR
2
4
and the solvent was evaporated to give a crude product identi-
Ðed as a mixture of 3 and 4. The mixture was taken up in
EtOH (20 mL) and irradiated (triturated) by ultrasounds. The
beige solid was Ðltered o† to give 4 (a, b and/or c). The Ðltrate
was evaporated in vacuo at 30 ¡C to give 3 (a, b and/or c).
([D ]acetone, d): 3.65È4.30 (AB system, J \ 18.5 Hz, 2H,
6
4@-H); 3.85 (s, 6H, 2 CH O); 5.40 (d, J \ 8.5 Hz, 1H, 3a-H);
3
5.75 (d, J \ 8.5 Hz, 1H, 6a-H), 6.90È8.10 (m, 8H, arom H). 13C
NMR ([D ]acetone, d): 42.2, 55.6, 56.6, 86.5, 113.3, 115.0È
6
163.0, 153.3, 158.8, 167.0.
For 3d (R \ NO ) the crude product was chromatographed
on a silica gel column (CH Cl ) to give a yellow solid.
2
Synthesis of (2E)-3-[3º-arylisoxazol-5º-yl]propenoic acid 5
2
2
Method
B.
Pure
3,3º-diaryl-3a,6a-dihydro-4-
Method A: Acidic hydrolysis of the cycloadducts 3a–d
(general procedure). To a solution of 3aÈd (0.25 mmol) in dry
acetonitrile (4.85 mL) was added with stirring 0.15 mL of
conc. HCl. The mixture was reÑuxed for 15 min, and then
poured into ice water (100 mL). The precipitate was Ðltered
and the crude product was puriÐed by recrystallization to
a†ord pure 5aÈd.
oxospiro[isoxazolino-5º,6-isoxazole[3,4-c]furanone] 4. The
reaction was carried out with 50 mg of hydroquinone, 0.24 g
(2.5 mmol) of 1, 7 mmol of 2 and 1 mL of Et N. Under these
3
conditions, only 4 (aÈd) was obtained.
3a: Yield 0.55 g (51%), m.p. 118È120 ¡C (Et O under ultra-
2
sonic irradiation at R.T.), white solid, anal. calcd. for
C
H NO : C, 66.97; H, 4.21; N, 6.51. Found C, 67.11; H,
12
9
3
4.28; N, 6.48. IR (KBr): l 1770, 1590 cm~1. 1H NMR
Method B: Basic hydrolysis of the cycloadducts 3a–d
(general procedure). To a solution of 3aÈd (0.25 mmol) in
ethanol (4.1 mL) was added 0.9 mL of 2 M NaOH. The
mixture was stirred and reÑuxed for 15 min. Usual aqueous
work up was followed by Ðltration to leave a product whose
spectral and analytical data were consistent with those
obtained by method A.
(CDCl , d): 3.45È3.90 (AB system, J \ 17.8 Hz, 2H, 4@-H);
3
6.35 (d, J \ 5.4 Hz, 1H, 4-H); 7.35 (d, J \ 5.4 Hz, 1H, 3-H);
7.20È7.85 (m, 5H, arom H). 13C NMR (CDCl , d): 43.1, 112.5,
3
125.5È131.1, 148.9, 158.1, 168.6.
3b: Yield 0.57 g (50%), m.p. 150È152 ¡C (Et O under ultra-
sonic irradiation at R.T.), white solid, anal. calcd. for
2
C
H
NO : C, 68.12; H, 4.84; N, 6.11. Found C, 68.23; H,
13 11
3
4.91; N, 6.03. IR (KBr): l 1785, 1600 cm~1. 1H NMR
Method C: Electrochemical oxidation of the cycloadducts
3a–d (general procedure). In the anodic compartment of a two-
compartment cell Ðtted with a saturated calomel reference
(SCE), was placed a spiroadduct 3 (0.25 mmol) dissolved in
acetonitrile (10 mL) and 0.1 M of tetraethylammonium per-
chlorate. The cathodic compartment was Ðlled with 10 mL of
pure electrolyte. A 3.5 cm2 platinum sheet was used as the
working electrode, and the electrolyses were performed under
argon atmosphere at a constant potential of ]2.1 (3a), ]2.0
(3b, 3d), or ]1.7 V (3c). The electrolyses were stopped when
the current reached 1.5 times the background current of the
cell (separately measured with no substrate added). After the
end of the electrolysis, acetonitrile was evaporated in vacuo,
and the compounds 5 were then extracted and puriÐed as
before, with thorough washing to eliminate residual traces of
the electrolyte salt.
(CDCl , d): 2.40 (s, 3H, CH ); 3.55È3.85 (AB system, J \ 17.7
3
3
Hz, 2H, 4@-H); 6.35 (d, J \ 5.5 Hz, 1H, 4-H); 7.25 (d, J \ 7.6
Hz, 2H, arom H); 7.35 (d, J \ 5.5 Hz, 1H, 3-H); 7.60 (d,
J \ 7.6 Hz, 2H, arom H). 13C NMR (CDCl , d): 21.3, 43.2,
3
112.5, 125.4È141.5, 148.9, 158.0, 168.6.
3c: Yield 0.6 g (49%), m.p. 132È134 ¡C (Et O under ultra-
2
sonic irradiation at R.T.), white solid, anal. calcd. for
C
H
NO : C, 63.68; H, 4.52; N, 5.71. Found C, 63.96; H,
13 11
4
4.47; N, 5.76. IR (KBr): l 1775, 1600 cm~1. 1H NMR
(CDCl , d): 3.85 (s, 3H, OCH ); 3.85È3.55 (AB system,
3
3
J \ 17.7 Hz, 2H, 4@-H); 6.35 (d, J \ 5.3 Hz, 1H, 4-H); 7.00 (d,
J \ 8.7 Hz, 2H, arom H); 7.40 (d, J \ 5.3 Hz, 1H, 3-H); 7.65
(d, J \ 8.7 Hz, 2H, arom H). 13C NMR (CDCl , d): 43.0, 55.2,
3
112.0, 114.2È164.9, 148.9, 157.2, 168.8.
3d: Yield 0.20 g (15%), m.p. 174È176 ¡C (Et O under ultra-
2
sonic irradiation at R.T.), yellow solid, anal. calcd. for
5a: Yield 0.054 g (quantitative) by methods A and B, 0.042
g (78%) by method C, m.p. 212È214 ¡C (propanol), white solid,
anal. calcd. for C H NO : C, 66.97; H, 4.21; N, 6.51. Found
C
H N O : C, 55.39; H, 3.10; N, 10.77. Found C, 55.65; H,
12
8 2 5
3.27; N, 10.49. IR (KBr): l 1775, 1595 cm~1. 1H NMR
12
9
3
(CDCl , d): 3.50È3.80 (AB system, J \ 17.8 Hz, 2H, 4@-H);
C, 67.15; H, 4.17; N, 6.33. IR (KBr): l 3180È2735, 1685, 1650,
3
6.30 (d, J \ 5.5 Hz, 1H, 4-H); 7.25 (d, J \ 5.5 Hz, 1H, 3-H);
1610 cm~1. 1H NMR (CDCl , d): 6.15 (d, J \ 12.7 Hz, 1H,
3
New J. Chem., 2000, 24, 471È476
475

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2-H); 7.05 (d, J \ 12.7 Hz, 1H, 3-H); 7.30È7.60 (m, 3H, arom
H); 7.65 (s, 1H, 4@-H); 7.75È7.95 (m, 2H, arom H); 8.95 (s, 1H,
H, 4.91; N 9.69. IR (KBr): l 1615 cm~1. 1H NMR (CDCl ,
3
d): 3.55È3.95 (AB part of ABX system, J \ 16.7 Hz, J \ 10.7
OH). 13C NMR (CDCl , d): 106.8, 120.6, 126.7È130.0, 162.1,
Hz, J \ 7.0 Hz, 2H, 4@-H); 5.90 (X part of ABX system,
J \ 10.7 Hz, J \ 7.0 Hz, 1H, 5@-H); 6.70 (s, 1H, 4-H); 7.30È
3
165.4, 168.5. HRMS m/z: 215 (100%).
5b: Yield 0.057 g (quantitative) by methods A and B, 0.048
g (84%) by method C, m.p. 240È241 ¡C (propanol), beige solid,
7.90 (m, 10H, arom H). 13C NMR (CDCl , d): 40.1, 74.1,
3
100.2, 126.7È130.5, 156.1, 162.4, 170.5.
anal. calcd. for C
H
NO : calcd. C, 68.12; H, 4.84; N, 6.11.
6b: Yield 0.060 g (75%) by method A, 0.072 g (91%) by
13 11
3
Found C, 68.24; H, 4.79; N, 6.01. IR (KBr): l 3085È2840,
method B, m.p. 139È140 ¡C (ethanol), beige solid, anal. calcd.
1685, 1635, 1610 cm~1. 1H NMR (CDCl , d): 2.40 (s, 3H,
for C
H
N O : C, 75.47; H, 5.70; N, 7.55. Found C, 75.75;
3
CH ); 6.20 (d, J \ 12.8 Hz, 1H, 2-H); 7.05 (d, J \ 12.8 Hz,
3
20 18
2
2
H, 5.68; N, 7.42. IR (KBr): l 1615 cm~1. 1H NMR (CDCl ,
3
d): 2.40 (s, 6H, 2 CH ); 3.50È3.90 (AB part of ABX system,
3
1H, 3-H); 7.30 (d, J \ 7.9 Hz, 2H, arom H); 7.65 (s, 1H, 4@-H);
7.75 (d, J \ 7.9 Hz, 2H, arom H); 9.90 (s, 1H, OH). 13C NMR
J \ 16.7 Hz, J \ 10.7 Hz, J \ 6.9 Hz, 2H, 4@-H); 5.85 (X part
(CDCl , d): 21.3, 106.7, 120.8, 126.6È140.2, 163.1, 165.0, 168.5.
of ABX system, J \ 10.7 Hz, J \ 6.9 Hz, 1H, 5@-H); 6.60 (s,
1H, 4-H); 7.10È7.40 (m, 4H, arom H); 7.60 (d, J \ 8.1 Hz, 2H,
arom H); 7.70 (d, J \ 8.1 Hz, 2H, arom H). 13C NMR
3
5c: Yield 0.061 g (quantitative) by methods A and B, 0.050
g (82%) by method C, m.p. 204È206 ¡C (propanol), white solid,
anal. calcd. for C
H
NO : calcd. C, 63.68; H, 4.52; N, 5.71.
(CDCl , d): 21.3, 40.2, 74.1, 100.1, 126.6È140.2, 156.1, 162.5,
13 11
4
3
Found C, 68.42; H, 4.60; N 5.62. IR (KBr): l 3190È2755, 1690,
170.5. HRMS m/z: 318 (100%).
1645, 1610 cm~1. 1H NMR (CDCl , d): 3.85 (s, 3H, OCH );
6c: Yield 0.065 g (74%) by method A, 0.078 g (89%) by
method B, m.p. 165È166 ¡C (ethanol), beige solid, anal. calcd.
3
3
6.15 (d, J \ 12.9 Hz, 1H, 2-H); 6.95 (d, J \ 8.5 Hz,
2H, arom H); 7.00 (d, J \ 12.9 Hz, 1H, 3-H); 7.55 (s, 1H, 4@-H);
7.70 (s, 1H, OH); 7.80 (d, J \ 8.5 Hz, 2H, arom H). 13C NMR
for C
H
N O : C, 68.57; H, 5.18; N, 7.99. Found C, 68.43;
20 18
2 4
H, 5.29; N, 8.13. IR (KBr): l 1615 cm~1. 1H NMR (CDCl ,
3
(CDCl , d): 55.2, 106.5, 114.2È162.7, 120.6, 161.0, 164.8, 168.6.
d): 3.55È3.85 (AB part of ABX system, J \ 16.6 Hz, J \ 10.6
3
5d: Yield 0.065 g (quantitative) by method A, 0.040 g (62%)
Hz, J \ 6.9 Hz, 2H, 4@-H); 3.85 (s, 6H, 2 OCH ); 5.85 (X part
3
by method B, 0.053 g (81%) by method C, m.p. 200È201 ¡C
of ABX system, J \ 10.6 Hz, J \ 6.9 Hz, 1H, 5@-H); 6.65 (s,
(propanol), yellow solid, anal. calcd. for C H N O : calcd.
C, 55.39; H, 3.10; N, 10.77. Found C, 55.46; H, 3.18; N, 10.68.
1H, 4-H); 6.80È7.10 (m, 4H, arom H); 7.65 (d, J \ 8.5 Hz, 2H,
arom H); 7.75 (d, J \ 8.5 Hz, 2H, arom H). 13C NMR
12
8 2 5
IR (KBr): l 3145È2795; 1700, 1635, 1610 cm~1. 1H NMR
(CDCl , d): 40.3, 55.2, 73.9, 99.9, 114.1È161.2, 155.7, 161.9,
3
([D ]acetone, d): 3.65 (s, 1H, OH); 6.40 (d, J \ 12.8 Hz, 1H,
170.4.
6
2-H); 7.15 (d, J \ 12.8 Hz, 1H, 3-H); 7.85 (s, 1H, 4@-H); 8.25 (d,
J \ 8.9 Hz, 2H, arom H); 8.45 (d, J \ 8.9 Hz, 2H, arom H).
13C NMR ([D ]acetone, 313 K, d): 107.5, 125.8È150.0, 162.5,
6
Notes and references
164.7, 167.1.
1
2
3
R. Fihi, K. Ciamala, J. Vebrel and N. Rodier, Bull. Soc. Chim.
Belg., 1995, 104, 55.
Synthesis of 3-aryl-5-[4º-(3º-aryl-4º,5º-dihydroisoxazolinyl)]-
isoxazole 6
P. Krogsgaard-Larsen and S. B. Christensen, Acta. Chem. Scand.
Ser. B, 1976, 30, 281.
Method A: Acidic hydrolysis (general procedure). Bis-adduct
4aÈc (0.25 mmol) in triÑuoroacetic acid (5 mL) was reÑuxed
for 2 h and then poured into an ice water mixture (100 mL).
After extraction with CH Cl (3 ] 10 mL), the organic phase
J. J. Hansen and P. Krogsgaard-Larsen, J. Chem. Soc., Perkin
T rans. 1, 1980, 1826.
4
5
P. Lugosi and J. Schawartz, T etrahedron, 1981, 37, 3061.
C. Roussel, K. Ciamala, P. Audebert and J. Vebrel, New J.
Chem., 1999, 23, 989.
2
2
was washed with water (2 ] 20 mL), dried (Na SO ) and
2
4
evaporated in vacuo. The crude products were puriÐed by
6
7
E. Schaw, J. Am. Chem. Soc., 1946, 68, 2510.
recrystallization from ethanol.
J. M. Saveant, in Advances in Electron T ransfer Chemistry, ed. P.
S. Mariano, JAI press, Greenwich, CT, USA, 1994, vol. 4, p. 53.
M. Robert and J.-M. Saveant, J. Am. Chem. Soc., 2000, 122, 514.
S. Antonello, M. Musumeci, D. D. M. Wayner and F. Maran, J.
Am. Chem. Soc., 1997, 119, 9541.
Method B: Basic hydrolysis (general procedure). To a solu-
tion of bis-adduct 4aÈc (0.25 mmol) in ethanol (4.1 mL) was
added 2 M NaOH (0.9 mL). The mixture was stirred at room
temperature for 2 h. After the usual work up, a crude mixture
was dissolved in ethanol (5 mL). Sulfuric acid (1 M, 0.9 mL)
was added and the mixture stirred at reÑux for 24 h. The reac-
tion was quenched by the addition of ice water (100 mL). After
work up in the same manner as in acidic hydrolysis, pure pro-
ducts 6 were obtained.
8
9
10 M. S. Workentin, F. Maran and D. D. M. Wayner, J. Am. Chem.
Soc., 1995, 117, 2120.
11 C. Grundmann and E. Kober, J. Am. Chem. Soc., 1955, 77, 2332.
12 C. Grundmann and R. Richter, J. Org. Chem., 1967, 32, 2308.
13 R. Huisgen and N. Mack, T etrahedron L ett., 1961, 17, 583.
14 K. C. Liu, B. R. Schelton and R. K. Howe, J. Org. Chem., 1980,
45, 3916.
15 R. H. Wiley and B. J. WakeÐeld, J. Org. Chem., 1960, 25, 546.
16 Y. H. Chiang, J. Org. Chem., 1971, 36, 2146.
17 D. Garreau and J. M. Saveant, J. Electroanal. Chem., 1972, 35,
309.
6a: Yield 0.050 g (69%) by method A, 0.067 g (93%) by
method B, m.p. 108È109 ¡C (ethanol), beige solid, anal. calcd.
for C
H
N O : C, 74.47; H, 4.86; N, 9.65. Found C, 74.53;
18 14
2 2
476
New J. Chem., 2000, 24, 471È476