Reactivity of arylnitrile oxides and C-aroyl-N-phenylnitrones with 3-methylenedihydro-(3H)-furan-2-one and itaconic anhydride

Article abstract of DOI:10.3987/COM-09-11681

1,3-dipolar cycloaddition is a powerful route for the synthesis of five-membered heterocycles. The [3+2] cycloadditions of some α-methylene-γ-buryrolactones, namely 3-methylenedihydro-(3H)-furan-2-one (1) and itaconic anhydride (2) were studied. Their rea

Full text of DOI:10.3987/COM-09-11681

HETEROCYCLES, Vol. 78, No. 8, 2009
1977
HETEROCYCLES, Vol. 78, No. 8, 2009, pp. 1977 - 1991. © The Japan Institute of Heterocyclic Chemistry
Received, 10th February, 2009, Accepted, 13th April, 2009, Published online, 13th April, 2009.
DOI: 10.3987/COM-09-11681
REACTIVITY OF ARYLNITRILE OXIDES AND C-AROYL-N-
PHENYLNITRONES WITH 3-METHYLENEDIHYDRO-(3H)-FURAN-2-
ONE AND ITACONIC ANHYDRIDE
Christophe Roussel, a† Kabula Ciamala,a* Joël Vebrel,a and Claude Richeb
aInstitute UTINAM UMR CNRS 6213, Faculty of Science and Technology,
University of Franche-Comté, 16 Route de Gray, F-25030 Besançon
bLaboratory of Crystallochemistry, Institute of Chemistry of Natural Products
(ICSN) CNRS, 1, Avenue de la terrasse, F-91198 Gif sur Yvette
†
Current address: Institute of Chemical Sciences and Engineering, Station 6,
Swiss Federal Institute of Technology, CH-1015 Lausanne, Switzerland
E-mail: kabula.ciamala@univ-fcomte.fr, christophe.roussel@epfl.ch
Abstract - 1,3-dipolar cycloaddition is a powerful route for the synthesis of five-
membered heterocycles. The [3+2] cycloadditions of some α-methylene--
buryrolactones, namely 3-methylenedihydro-(3H)-furan-2-one (1) and itaconic
anhydride (2) were studied. Their reactions with arylnitrile oxides (3) and C-
aroyl-N-phenylnitrones (7) proceed with complete regioselectivity. From a
stereochemical point of view, the addition of arylnitrile oxides (3) leads to the
unique spiroheterocycles (4-5). Actually, a single stereocenter is generated during
the reaction. In the particular case of p-nitrophenylnitrile oxide (3d), only the
diacidic form (10d) of the spiroheterocyle (5d) was isolated. In contrast, the
addition of C-aroyl-N-phenylnitrones (7) produces a couple of diastereoisomers,
since two stereocenters are generated simultaneously. Nevertheless, the reaction is
regioselective and stereospecific leading also to the single spiroheterocycles (19-
20). The proposed stereochemistry of spiranic compounds (19d) and (20d) has
been corroborated by two single crystal X-ray crystallographic analysis.
INTRODUCTION
Pharmaceutical industry is much interested in molecules presenting biological activities. Specific
syntheses of α-methylene-γ-butyrolactones with cytotoxic, phytotoxic, antitumoral and bactericidal
properties have been reviewed.1 In addition, simple chemical modifications performed at the methylene

1978
HETEROCYCLES, Vol. 78, No. 8, 2009
group have been carried out and the biological activity of the resulting compounds has been compared to
that of the original molecules.2-5 For example, the transformation of dehydroleucodine into 11,13-
dihydro-dehydroleucodine (=CH2→CH3) decreases cytotoxic effects without significant alteration of the
original therapeutic properties.2 One of the possibilities to chemically modify the methylene group is the
[3+2] cycloaddition, affording bicyclic spiranic heterocycles.6-12 As an example, cyclopropyl spiranic
lactones presenting anticonvulsant properties have been prepared from the reaction of unsaturated
lactones with diazomethane.11
Since several years we have focused on the reactivity of methylene-γ-butyrolactones towards several
1,3-dipoles such as nitrones,13,14 nitrile oxides15-17 and diazoalkanes.18,19 We particularly paid attention to
the role played by the substituents of the dipolar entities on both chemical reactivity and stereochemistry.
We have demonstrated that the reactions of linear C-N-O 1,3-dipoles such as arylnitrile oxides with
achiral γ-methylene-γ-butyrolactones proceed with complete regioselectivity. The [3+2] cycloadditions
lead to unique spiroheterocycles,15-17 only one stereocenter being generated from the prostereogenic
carbon atom of the methylene group (Scheme 1). To the best of our knowledge, except our work,15 only
two references relate the reactivity of arylnitrile oxides with simple α-methylene-γ-butyrolactones. The
[3+2] cycloadditions of phenylnitrile oxide (3a) and p-tolylnitrile oxide (3b) with 3-methylenedihydro-
(3H)-furan-2-one (1)20 and itaconic anhydride (2)21 have been reported (Scheme 1).
R
R
C N O
X
3a-b

X
O
O
N
O
O
O
1
: X = CH2
2: X = CO
4a: X = CH2, R= H, 41%a
4b: X = CH2, R= Me, 56%b
5a
: X = CO, R= H, 75%
c
Scheme 1. [3+2] Cycloadditions of phenyl- (3a) and p-tolylnitrile oxide (3b) with 3-methylenedihydro-
(3H)-furan-2-one (1)15,20 and itaconic anhydride (2).21 a) in refluxing benzene for 5 h,20 b) in Et2O at room
temperature for 48 h,15 c) in Et2O at room temperature for few minutes and refluxed for 30 min.21 Note
that recrystallisation of (5a) in water affords the diacidic form of the anhydride moiety (10a). * represents
a center of chirality.
When going towards bended C-N-O 1,3-dipoles like nitrones, the reactions proceed differently as each
reactant possesses a prostereogenic carbon atom. For example, the reactions of γ-methylene-γ-
butyrolactones with C-aroyl-N-phenylnitrones (7) also present complete regioselectivities but lead to two
diastereoisomers (8) and (9) as depicted in Scheme 2.13

HETEROCYCLES, Vol. 78, No. 8, 2009
1979
O
Ar
O
O
C
H
C
Ar
Ar
H
O
*
+
O
+
N
*
Ph
N
O
*
Ph
O
N
O
O
O
O
O
Ph
7a-d
6
8a: Ar = Ph, 32%
9a: Ar = Ph, 22%
8b: Ar = p-Me-C6H4, 47%
8c: Ar = p-MeO-C6H4, 23%
8d: Ar = p-NO2-C6H4, 21%
9b: Ar = p-Me-C6H4, 25%
9c: Ar = p-MeO-C6H4, 34%
9d: Ar = p-NO2-C6H4, 49%
Scheme 2. [3+2] Cycloadditions of C-aroyl-N-phenylnitrones (7a-d) with 3-methylenephthalide (6). 24 h
in EtOAc at room temperature. The amount of each diastereoisomer depends on Ar. *represents a chiral
center.
In these examples, the diastereoselectivity of the reactions was explained by the different interactions
occurring during the establishment of the transition states. Similar studies involving (7a) and several
γ-methylene-γ-butyrolactams (derived from (6)) showed the same behaviour.22 In contrast, the [3+2]
cycloadditions of (7a) with various α-methylene-γ-butyrolactams (derived from (1)) were found to be
stereospecific,23 pointing out the important role played by these secondary interactions.
Herein, we report a reinvestigation of the reactivity of substituted arylnitrile oxides (3a-d), bearing either
electron donating or withdrawing groups, with 3-methylenedihydro-(3H)-furan-2-one (1) and itaconic
anhydride (2) to complete and generalise the previously reported studies. In addition, we extended our
study on the reactivity of C-aroyl-N-phenylnitrones (7) towards the dipolarophiles (1) and (2) with the
following aims : (i) to figure out the factors governing the stereoselectivity of the reactions and (ii) to
compare the stereochemistry of the [3+2] adducts with those resulting from the reactions of similar
α-methylene-γ-butyrolactams with the same 1,3-dipoles.23
RESULTS AND DISCUSSION
Cycloaddition of arylnitrile oxides
The [3+2] cycloadditions of 3-methylenedihydro-(3H)-furan-2-one (1) and itaconic anhydride (2) with
arylnitrile oxides (3a-d) led to unique adducts corresponding to the expected five-membered
spiroheterocyles (4-5), except for the reaction involving (2) and (3d). The reactions proceed with 100%
regioselectivity and spiroheterocyles (4-5) were isolated as racemates (Scheme 3).
The regiochemistry depicted in Scheme 3 was ascertained by 13C NMR spectroscopy. The chemical shift
of the spiranic carbon atom C3,5’ (~84 ppm/TMS for (4) and ~87 ppm/TMS for (5)) is in agreement with
vicinity of the isoxazolinic oxygen atom, as already reported.20

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HETEROCYCLES, Vol. 78, No. 8, 2009
The reactions were carried out at room temperature in the presence of hydroquinone as reported
previously.13,14,16-19 The reaction of (1) with arylnitrile oxides (3) proceeded with good yields (except for
(4d)) compared to that in refluxing benzene (71% instead of 41% for (4a)).20
R
R
R
C N O
OH
1
X
2
5X
1O
4
3
4'
4'
3'
N2'
3'

3a-d
5'
+
5'
3
X
N2'
2
1'

1'
O
O
O
O
OH
O
O
4a: X = CH2, R= H, 71%a
4b: X = CH2, R= Me, 64%a
10d: X = CO, R= NO2, 20%b
1: X = CH2
2: X = CO
4c: X = CH2, R= OMe, 50%a
4d: X = CH2, R= NO2, 26%a
5a: X = CO, R= H, 73%b
5b: X = CO, R= Me, 64%b
5c: X = CO, R= OMe, 60%b
5d: X = CO, R= NO2, 0%b
Scheme 3. [3+2] Cycloadditions of arylnitrile oxides (3a-d) with 3-methylenedihydro-(3H)-furan-2-one
(1) and itaconic anhydride (2). a) 24 h in Et2O at room temperature, b) 24 h in EtOAc at room
temperature. ((2) is not soluble in Et2O). *represents a center of chirality.
The classic procedure for generating arylnitrile oxides (3) in situ from arylhydroximoyl chlorides (by
addition of triethylamine)24 used for the reaction involving (1) was not suitable with itaconic anhydride
(2). After addition of the base, a degradation occurred, even with DABCO or substituted pyridines
(pyridine catalyzes arylnitrile oxide dimerization).25 To overcome any degradation, arylnitrile oxides (3a-
d) were first generated with triethylamine in a separate flask and then added to itaconic anhydride (2).
This procedure, different from the thermal generation of arylnitrile oxides from arylhydroximoyl
chlorides,21 afforded also the adducts (5) in good yields (similar yield for (5a), Schemes 1 and 3), except
for (5d).
Another important point concerns the reaction of (2) with p-nitrophenylnitrile oxide (3d) and especially
the structure of the resulting product. Compared to the isolated adducts (5a-c), the IR analyses of the
obtained product revealed the disappearance of the vibrations at ~1870 and 1790 cm-1 (C=O anhydride)
and the appearance of vibrations in the range between 3305 - 2720 cm-1 (associated OH) and at 1710 cm-1
1
(carboxylic C=O). The H NMR spectrum displayed two exchangeable protons with D2O and MS
analyses (EI at 70 eV) gave a molecular weight of 294 g/mol, corresponding to the diacidic form of the
expected adduct (5d) (276 g/mol). Further comparisons of these spectroscopic data with those of the
hydrolysis products of (5a-c), confirmed that (10d) arose from (5d) by an in situ opening of the anhydride
moiety.

HETEROCYCLES, Vol. 78, No. 8, 2009
1981
Cycloaddtions of C-aroyl-N-phenylnitrones
Goti and co-workers have reported the reaction of the C,N-diphenylnitrone with -methylene--
butyrolactone (1) in refluxing benzene or toluene.12 The cycloaddition afforded two diastereoisomers
5-spirosubstituted isoxazolidines with high selectivity (90:10) or (80:20) respectively (Scheme 4).
The 1,3-dipolar cycloaddition of C-benzoyl-N-phenylnitrone with -methylenelactams exclusively gave a
single cycloaddition in toluene via an-endo transition state23 (Scheme 4).
Ph
Ph
Ph
O
O
80°C or 110°C
+
+
N
N
N
O
O
Ph
Ph
O
Ph
Ph
O
O
O
O
O
90:10 or 80:2012
13
11
1
12
Ph
Ph
Ph
O
O
O
50°C
+
+
N
N
N
NMe
NMe
O
Ph
Ph
N
O
Me
14
11
15
85:1523
16
COPh
COPh
COPh
O
O
80°C
+
+
N
N
O
17
N
O
NMe
NMe
O
Ph
Ph
Ph
O
N
Me
14
7a
100:023
18
Scheme 4. [3+2] Cycloadditions of a) C,N-diphenylnitrone with 3-methylenedihydro-(3H)-furan-2-one12
(1) and 1-methyl-3-methylenepyrrolidin-2-one (14).23 b) C-benzoyl-N-phenylnitrones (7a) with 1-methyl-
3-methylenepyrrolidin-2-one (14).23
For comparison, the reactions of C-aroyl-N-phenylnitrones (7a-d) with 3-methylenedihydro-(3H)-furan-
2-one (1) and itaconic anhydride (2) were also investigated. Independently of the nature of the
cycloaddition partners, the reactions proceeded with complete regioselectivity and stereospecificity.26,27
The spiranic adducts (19) and (20) were isolated as racemates and the stereochemical features were
established by NMR and X-ray crystallographic analysis (Scheme 5).
O
Ar
Ar
H
C
O
O
O
O
+
4'
3'
4'
+
1'
2' 5'
N
2
2
X
2'
1
5
5'
N
1
5
O
N
C
O
1'
3
Ph
O
3
O
3'
Ph
Ph
Ar
O
O
4
4
X
X
H
1: X = CH2
2: X = CO
7a-d
O
19-20
19a: X = CH2, Ar = Ph, 43%
100:0
19'-20'
20a: X = CO, Ar = Ph, 92%
19b: X = CH2, Ar = p-Me-C6H4, 31% 20b: X = CO, Ar = p-Me-C6H4, 77%
19c: X = CH2, Ar = p-MeO-C6H4, 33% 20c: X = CO ; Ar = p-MeO-C6H4, 79%
19d: X = CH2, Ar = p-NO2-C6H4, 42% 20d: X = CO ; Ar = p-NO2-C6H4, 90%
Scheme 5. [3+2] Cycloadditions of C-aroyl-N-phenylnitrones (7a-d) with 3-methylenedihydro-(3H)-
furan-2-one (1) and itaconic anhydride (2). 24 h in EtOAc at room temperature.

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HETEROCYCLES, Vol. 78, No. 8, 2009
Again, the reactions were carried out at room temperature in the presence of hydroquinone. Whereas the
[3+2] cycloaddition of itaconic anhydride (2) with C-aroyl-N-phenylnitrones (7) proceeded in good yields,
3-methylenedihydro-(3H)-furan-2-one (1) remained less reactive, as already observed with ethyl
diazoacetate.18,19
The regioselectivity of these [3+2] cycloadditions were accessed by 1H NMR spectroscopy. The 1H NMR
spectra of (19) and (20) display an ABX system corresponding to the protons attached on the
isoxazolidinic ring (H4’a, H4’b and H3’). This pattern is in favour of formation of regioisomers (19) and
(20). For the hypothetical regioisomers (19’) and (20’), the proton H3’ should appear as a singlet. Further
13
confirmation of the regiochemistry came from C-1H HSQC NMR. As shown in Figure 1, the spiranic
carbon atom C3,5’ was easily identified at 80 ppm/TMS as it is the sole sp3 quaternary carbon atom which
13
therefore, do not present any correlation with protons. Extended C NMR studies gave a chemical shift
for the spiranic carbon atoms between ~82 and ~84 ppm for (19) and (20), in agreement with the
proximity of the isoxazolidinic oxygen atom9,12,13 (Figure 2). In addition, 13C-1H HSQC NMR performed
on spiroheterocycles (19) allows the correct attribution of the chemical shifts of C4 and C4’. Whereas
these chemical shifts are rather similar, the main difference between C4 and C4’ stems from the spin
multiplicity of their respective born protons. Actually, C4 bears the AB part of an ABXX’ system (H4a,
H4b and H5a, H5b) and C4’, the AB part of an ABX system (H4’a, H4’b and H3’). Based on figure 1, the
respective chemical shifts of C4 and C4’ were found to be ~34 and ~37 ppm/TMS respectively. In contrast,
for spiroadducts (20), C4 and C4’ could be easily distinguished by 13C NMR. Since C4 is directly linked to
the anhydride carbonyl, it is therefore more deshielded (C4 and C4’ at ~41.0 and ~37 ppm/TMS respectively).
Figure 1. 13C-1H HSQC NMR spectrum of (19b)

HETEROCYCLES, Vol. 78, No. 8, 2009
1983
From a stereochemical point of view, the reactions generate two stereocenters C3,5’ and C3’ from the two
prostereogenic carbon atoms of (1-2) and (7), respectively. Indeed, two possible diastereoisomers as
racemates (the two dipolarophilic faces are equivalent) could be envisaged if the stereochemistry of the
nitrones (7) is conserved. As confirmed by the X-ray studies performed on both (19d) and (20d), the
retention of the original relative (Z) configuration of the nitrones (7)28,29 is in favour of a concerted
mechanism30 (Figure 2). Thus, according to the Woodward-Hoffmann rules,31 the stereospecificity of the
reaction could be figured out from endo-C=O and exo-C=O transition states as depicted in scheme 6.12,13
(19d)
(20d)
Figure 2. Ortep drawing of molecule (19d) and (20d), drawn by program PLATON.32 Displacement
ellipsoids are shown at the 20% probability level. Comparison of torsion angle values shows that the
isoxazolidinic ring adopts the same half-chair conformation, in which atoms N2 and C3 are respectively
deviated, by –0.347(3) and 0.293(3) Å from the mean plane of the other three atoms in (19d), by -
0.288(2) and 0.329(2) Å, in (20d).
O
O
O
N
O
O
N
O
X
O
X
O
O
X
O
X
O
O
O
O
19-20
19-20
N
N
O
O
unfavourable
exo -C=O approach unfavourable
favourable
endo -C=O approach favourable
Scheme 6. Endo-C=O and exo-C=O transition states for the reaction of C-aroyl-N-phenylnitrones (7a-d)
with 3-methylenedihydro-(3H)-furan-2-one (1) and itaconic anhydride (2).

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HETEROCYCLES, Vol. 78, No. 8, 2009
As shown in Figure 2, the anti-periplanar relationship between the dipolar and lactonic carbonyl groups is
in favour of the endo-C=O approach, scheme 6. Whereas the endo-C=O transition state provides some
secondary orbital interactions between the N-phenyl group of the nitrone and the carbonyl group of the
lactone, the exo-C=O transition state does not afford such stabilising effects.12 Nevertheless, the
difference between these two transition states could not explain the stereospecificity of the reaction. For
example, the [3+2] cycloaddition of C,N-diphenylnitrone with (1), is stereoselective, the endo-C=O
product being the major one.12 Indeed, as the two dipolarophiles under study lead to the same
diastereoisomers, the stereospecificity of our reactions should stem from the presence of the
supplementary C=O born by the C-aroyl-N-phenylnitrone compared to C,N-diphenylnitrone. As shown in
scheme 6, the exo-C=O transition state presents also the electrostatic repulsion of the two carbon-oxygen
dipoles born by the reactants. This electrostatic repulsion could then be considered as the main factor that
orientates the reaction through the generation of the endo-C=O spiroadducts (19) and (20) only.
CONCLUSION
We revisited the reactivity of arylnitrile oxides with simple α-methylene-γ-butyrolactones, using
substituted 1,3-dipoles to complete and generalise the previous reported studies. The reactions involving
both 3-methylene-(3H)-furan-2-one and itaconic anhydride lead to the expected spiroheterocycles, except
for the reaction of itaconic anhydride with p-nitrophenylnitrile oxide which affords directly the diacidic
form of the spiranic compound. Whatever the dipolarophile, the 1,3-dipolar cycloadditions are entirely
regioselective, the observed regioselectivity being in total agreement with other studies reported
previously. The [3+2] cycloadditions of the same dipolarophiles (1) and (2) with C-aroyl-N-
phenylnitrones are again fully regioselective and stereospecific. Based on X-ray diffraction studies, the
stereospecificity of the reaction was explained by the repulsion of the lactonic and dipolar oxygen atoms
during the establishment of the transition state.
EXPERIMENTAL
The cycloadditions were carried out under nitrogen atmosphere using standard Schlenk techniques. TLC
plates, DC-Alufolien Kieselgel 60 F254, were from Merck. Melting points were measured on an Electro-
1
13
thermal IA 9200 and are not corrected. H and C NMR spectra were recorded on Bruker AC 200 [200
MHz (1H) and 50 MHz (13C)]. HSQC NMR spectra were recorded on a Bruker Avance 300 spectrometer
[300 MHz (1H) and 75 MHz (13C)]. Chemical shifts were measured relative to TMS. IR spectra were
recorded on a Bio-Rad FTS-7 spectrometer. Mass spectrometry experiments were run on a NERMAG R
1010 H apparatus under electronic impact at 70 eV. Elemental analyses (C, H, N) were conducted on a
Leco Elemental CHN 900; values were in satisfactory agreement with the calculated ones (0.30%).

HETEROCYCLES, Vol. 78, No. 8, 2009
1985
Starting materials.
3-Methylenedihydro-(3H)-furan-2-one (1) was obtained from dihydro-(3H)-furan-2-one following the
literature procedure33 (xylene was replaced by anhydrous toluene in the second step). (1) was further
purified by column chromatography34 or by distillation under reduced pressure.35 Itaconic anhydride (2)
was purshased from Aldrich. Arylnitrile oxides (3a-d), were obtained in situ by addition of triethylamine
to arylhydroximoyl chlorides,24 synthetised according to the literature.36,37 C-Aroyl-N-phenylnitrones (7a-
d) were obtained from p-substituted-2-bromoacetophenone pyridinium salts.38 p-Substituted-2-
bromoacetophenone pyridinium salts were synthetised as follows: To 1 equiv. of p-substituted-2-bromo-
acetophenones dissolved in 100 mL of dry acetone was slowly added 1 equiv. of pyridine. The resulting
mixture was stirred vigorously for 10 min. The formed precipitate was filtered, washed with 50 mL of dry
acetone, dried and used without further purification (yields: 77%, 70%, 55%, 89% for (a-d) respectively).
Cycloaddition of 3-methylenedihydro-(3H)-furan-2-one (1) with arylnitrile oxides (3a-d)
In a Schlenk tube containing 3-methylenedihydro-(3H)-furan-2-one (1) (0.49 g, 5 mmol) and 0.05 g (0.45
mmol) of hydroquinone in anhydrous Et2O (20 mL), was added under stirring, arylhydroximoyl chlorides
(7 mmol). After cooling the mixture at 0 °C, 1 mL (7 mmol) of Et3N was added dropwise and after
purging with dry N2, the reaction was carried out at room temperature for 24 h. After reaction, the
solution was first filtered on a glass frit to get rid of triethylammonium chloride (resulting from the
dechlorination of arylhydroximoyl chlorides). The filtrate was evaporated under reduced pressure leading
to a solid. The two collected solids were dissolved in 20 mL of CH2Cl2 and washed with distilled water
(320 mL). The organic phase was dried on Na2SO4 and evaporated under reduced pressure; the crude
products were purified by recrystallisation from EtOH.
3’-Phenylspiroisoxazolino[5’:3]dihydro-(3H)-furan-2-one (4a)
White solid; yield 0.76 g (71%, lit., 41%20); mp 132-134 °C (lit., 132-133 °C20); IR (KBr) 1775, 1580 cm-
1
1; H NMR (CDCl3) δ/TMS 2.30-2.80 (m, 2H), 3.30-4.00 (AB, 2H J=16.9 Hz), 4.35-4.60 (m, 2H), 7.30-
7.75 (m, 5H); 13C NMR (CDCl3) δ/TMS 35.1, 41.9, 65.8, 84.2, 126.7-130.5, 155.9, 173.9; Anal. Calcd for
C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.58; H, 4.91; N, 6.57.
3’-(4-Methylphenyl)spiroisoxazolino[5’:3]dihydro-(3H)-furan-2-one (4b)
1
White solid; yield 0.74 g (64%, lit., 56%15); mp 128 °C (lit., 128 °C15); IR (KBr) 1775, 1580 cm-1; H
NMR (CDCl3) δ/TMS 2.40 (s, 3H), 2.30-2.80 (m, 2H), 3.30-4.00 (AB, 2H, J=16.8 Hz), 4.30-4.60 (m, 2H),
13
7.20 (d, 2H, J=8.0 Hz), 7.55 (d, 2H, J=8.0 Hz); C NMR (CDCl3) δ/TMS 21.3, 35.0, 42.0, 65.8, 84.0,
125.3-140.8, 155.8, 174.0; Anal. CalcdforC13H13NO3:C, 67.52;H,5.67;N, 6.06. Found:C, 67.69;H, 5.61;N, 6.12.
3’-(4-Methoxyphenyl)spiroisoxazolino[5’:3]dihydro-(3H)-furan-2-one (4c)
Colorless solid; yield 0.62 g (50%); mp 137-139 °C; IR (KBr) 1775, 1600 cm-1; 1H NMR (CDCl3) δ/TMS

1986
HETEROCYCLES, Vol. 78, No. 8, 2009
2.30-2.80 (m, 2H), 3.85 (s, 3H), 3.25-4.00 (AB, 2H, J=16.8 Hz), 4.35-4.60 (m, 2H), 6.95 (d, 2H, J=8.8
13
Hz), 7.60 (d, 2H, J=8.8 Hz); C NMR (CDCl3) δ/TMS 35.0, 42.1, 55.2, 65.8, 83.9, 114.0-161.3, 155.5,
174.1; Anal. Calcd for C13H13NO4: C, 63.15; H, 5.30; N, 5.67. Found: C, 62.89; H, 5.41; N, 5.79.
3’-(4-Nitrophenyl)spiroisoxazolino[5’:3]dihydro-(3H)-furan-2-one (4d)
1
Yellow solid; yield 0.34 g (26%); mp 208-209 °C, IR (KBr) 1785, 1610 cm-1, H NMR (acetone-d6)
δ/TMS 2.60-2.90 (m, 2H), 3.70-4.10 (AB, 2H, J=17.5 Hz), 4.40-4.70 (m, 2H), 8.00 (d, 2H, J=8.8 Hz),
13
8.35 (d, 2H, J=8.8 Hz); C NMR (acetone-d6) δ/TMS 35.2, 42.0, 66.8, 86.8, 124.8-135.9, 156.3, 174.6;
Anal. Calcd for C12H10N2O5: C, 54.97; H, 3.84; N, 10.68. Found: C, 55.23; H, 3.89; N, 10.53.
Cycloaddition of itaconic anhydride (2) with arylnitrile oxides (3a-d)
To a magnetically stirred solution of 3.5 mmol of arylhydroximoyl chlorides in 15 mL of EtOAc at 0 °C,
was added 0.4 mL of Et3N (2.9 mmol). After 5 min, the solution was added dropwise through a glass
fritted disk (to get ride of the formed Et3NHCl) to a solid mixture of 0.28 g (2.5 mmol) of itaconic
anhydride (2) and 0.05 g (0.45 mmol) of hydroquinone contained in a Schlenk tube cooled at –15 °C. The
glass fritted disk was rinsed with 5 mL of EtOAc. After purging with nitrogen, the reaction was stirred at
room temperature for 24 h. After reaction, the solvent was evaporated under reduced pressure; the crude
products were purified by recrystallisation from CH2Cl2-Et2O (1:1).
3’-Phenylspiroisoxazolino[5’:3]succinic anhydride (5a)
Colorless solid; yield 0.42 g (73%, lit., 75%21); mp 146-148 °C (lit., 147-149 °C21); IR (KBr) 1865, 1800,
1605 cm-1; 1H NMR (acetone-d6) δ/TMS 3.45-3.90 (AB, 2H, J=19.2 Hz), 3.90-4.30 (AB, 2H, J=17.9 Hz),
7.45-7.85 (m, 5H); 13C NMR (acetone-d6) δ/TMS 42.5, 45.0, 87.5, 128.5-132.3, 158.3, 169.4, 172.9; Anal.
Calcd for C12H9NO4: C, 62.34; H, 3.92; N, 6.06. Found: C, 62.48; H, 4.19; N, 5.81.
3’-(4-Methylphenyl)spiroisoxazolino[5’:3]succinic anhydride (5b)
Colorless solid; yield 0.39 g (64%); mp 170-172 °C; IR (KBr) 1870, 1785, 1600 cm-1; 1H NMR (acetone-
d6) δ/TMS 2.40 (s, 3H), 3.45-3.85 (AB, 2H, J=19.1 Hz), 3.85-4.25 (AB, 2H, J=17.8 Hz), 7.35 (d, 2H, J=
7.9 Hz), 7.65 (d, 2H, J=7.9 Hz); 13C NMR (acetone-d6) δ/TMS 22.1, 42.5, 45.1, 87.3, 127.1-142.6, 158.2,
169.4, 172.9; Anal. Calcd for C13H11NO4: C, 63.67; H, 4.52; N, 5.71. Found: C, 63.60; H, 4.61; N, 5.69.
3’-(4-Methoxyphenyl)spiroisoxazolino[5’:3]succinic anhydride (5c)
White solid; yield 0.39 g (60%); mp 169-171 °C; IR (KBr) 1875, 1795, 1605 cm-1; 1H NMR (acetone-d6)
δ/TMS 3.35-3.80 (AB, 2H, J=19.0 Hz), 3.85 (s, 3H), 3.80-4.20 (AB, 2H, J=18.0 Hz), 7.00 (d, 2H, J= 8.9
13
Hz), 7.70 (d, 2H, J= 8.9 Hz); C NMR (acetone-d6) δ/TMS 42.5, 45.2, 56.5, 87.2, 115.8-163.3, 157.8,
169.5, 173.0; Anal. Calcd for C13H11NO5: C, 59.77; H, 4.24; N, 5.36. Found: C, 59.94; H, 4.19; N, 5.42.

HETEROCYCLES, Vol. 78, No. 8, 2009
1987
Alkaline treatment of 3’-arylspiroisoxazolino[5’:3]succinic anhydride (5a-c)
To a solution of spiroadducts 5a-c (0.25 mmol) in 4.1 mL of EtOH was added 0.9 mL of NaOH (2 M). The
mixture was refluxed for 30 min, poured into an ice-water mixture (100 mL) and acidified with
hydrochloric acid (or sulfuric acid). After extraction with CH2Cl2 (20 mL), the organic phase was washed
with distilled water (220 mL), dried (Na2SO4) and evaporated in vacuo. The crude products were purified
by recrystallization from distilled water.
Isoxazolino-3’-phenyl-5’-carboxy-5’-ethanoic acid (10a)
Beige solid; yield 0.057 g (92%); mp 206-207 °C (lit., 197 °C21); IR (KBr) 2720-3285, 1705, 1605 cm-1;
1H NMR (acetone-d6) δ/TMS 3.00-3.40 (AB, 2H, J=16.7 Hz), 3.50-4.20 (AB, 2H, J=17.2 Hz), 7.30-7.90
13
(m, 5H), 9.30 (s, 2H); C NMR (acetone-d6) δ/TMS 41.0, 44.0, 86.6, 127.5-131.0, 157.4, 171.2, 171.3;
Anal. Calcd for C12H11NO5: C, 57.83; H, 4.45; N, 5.62. Found: C, 57.99; H, 4.33; N, 5.73.
Isoxazolino-3’-(4-methylphenyl)-5’-carboxy-5’-ethanoic acid (10b)
1
Beige solid; yield 0.062 g (94%); mp 192-194 °C; IR (KBr) 2810-3280, 1705, 1610 cm-1; H NMR
(acetone-d6) δ/TMS 2.40 (s, 3H), 3.00-3.40 (AB, 2H, J=16.8 Hz), 3.50-4.20 (AB, 2H, J=17.5 Hz), 7.30 (d,
2H, J= 8.0 Hz), 7.65 (d, 2H, J= 8.0 Hz), 8.35 (s, 2H); 13C NMR (acetone-d6) δ/TMS 21.3, 41.0, 44.1, 86.4,
127.5-141.2, 157.3, 171.2, 171.3; HRMS (EI, 70 eV) m/z 263 (I= 0.50%) M+• , 245 (I= 4.24%) M+•-(H2O),
218 (I= 0.50) M+• -(COOH), 201 (I= 4.40%) M+•-(COOH) -(OH), 160 (I= 100%) M+•-(COOH) -(OH) -
(CH=C=O), 131 (I= 26,03%) M+• -(COOH) -(OH) -(CH=C=O) -(CHO) a; Anal. Calcd for C13H13NO5: C,
59.31; H, 4.98; N, 5.32. Found: C, 59.16; H, 5.07; N, 5.39.
a) determined according to the literature 39
Isoxazolino-3’-(4-methoxyphenyl)-5’-carboxy-5’-ethanoic acid (10c)
1
Beige solid; yield 0.065 g (93%); mp 199-200 °C; IR (KBr) 2760-3280, 1705, 1605 cm-1; H NMR
(acetone-d6) δ/TMS 3.00-3.40 (AB, 2H, J=16.9 Hz), 3.85 (s, 3H), 3.50-4.20 (AB, 2H, J=17.4 Hz), 7.00 (d,
2H, J= 8.8 Hz), 7.70 (d, 2H, J= 8.8 Hz), 9.10 (s, 2H); 13C NMR (acetone-d6) δ/TMS 41.0, 44.2, 55.7, 86.2,
114.9-162.1, 156.9, 171.2, 171.4; Anal. Calcd for C13H13NO6: C, 55.91; H, 4.69; N, 5.02. Found: C,
56.10; H, 4.71; N, 4.97.
Isoxazolino-3’-(4-nitrophenyl)-5’-carboxy-5’-ethanoic acid (10d) b
1
Yellow solid; yield 0.15 g (20%); mp 110-112 °C; IR (KBr) 2720-3305, 1710, 1605 cm-1; H NMR
(acetone-d6) δ/TMS 3.10-3.45 (AB, 2H, J=16.9 Hz), 3.70-4.30 (AB, 2H, J=17.5 Hz), 8.05 (d, 2H, J= 8.9
13
Hz), 8.40 (d, 2H, J= 8.9 Hz); C NMR (acetone-d6) δ/TMS 41.7, 44.2, 88.5, 123.6-136.7, 157.3, 171.9;
Anal. Calcd for C12H10N2O7: C, 48.99; H, 3.43; N, 9.52. Found: C, 49.26; H, 3.49; N, 9.46.
b) by in situ ring opening during cycloaddition

1988
HETEROCYCLES, Vol. 78, No. 8, 2009
Cycloadditions of 3-methylenedihydro-(3H)-furan-2-one (1) and itaconic anhydride (2) with C-aroyl-N-
phenylnitrones (7a-d)
In a Schlenk tube were added 5 mmol of methylene-lactone (1-2), 5 mmol of C-aroyl-N-phenylnitrones
(7a-d), 0.05 g (0.45 mmol) of hydroquinone and 20 mL of EtOAc. The mixture was stirred at room
temperature for 24 h under nitrogen atmosphere and the solvent removed under reduced pressure leading
to a crude oil. For spiroheterocyles (19), EtOH (20 mL) was added to the crude oil and the mixture
subjected to ultrasonication. The resulting solids were recrystallised from EtOH. For spiroheterocycles
(20), Et2O (20 mL) was added to the crude oil and the mixture was subjected to ultrasonication. The
resulting solids were recrystallised from a mixture of CH2Cl2-Et2O (1:1).
3’-Benzoyl-2’-phenyl-2’,3’-dihydrospiroisoxazolino[5’:3]dihydro-(3H)-furan-2-one (19a)
1
Beige solid; yield 0.70 g (43%); mp 159-160 °C; IR (KBr) 1775, 1685 cm-1; H NMR (CDCl3) δ/TMS
2.40-2.75 (m, 2H), 2.85-3.10 (AB part of an ABX, 2H, JAX=4.2, JBX=7.5, JAB=12.4 Hz), 4.30-4.55 (m,
2H), 5.55 (X part of an ABX, 1H, JAX=4.2, JBX=7.5), 6.95-8.20 (m, 10H); 13C NMR (CDCl3) δ/TMS 34.4,
37.2, 65.9, 69.0, 82.5, 115.1-148.9, 174.6, 195.3; Anal. Calcd for C19H17NO4: C, 70.58; H, 5.30; N, 4.33.
Found: C, 70.87; H, 5.41; N, 4.34.
3’-(4-Methylbenzoyl)-2’-phenyl-2’,3’-dihydrospiroisoxazolino[5’:3]dihydro-(3H)-furan-2-one (19b)
1
Beige solid; yield 0.52 g (31%); mp 142-143 °C; IR (KBr) 1775, 1680 cm-1; H NMR (CDCl3) δ/TMS
2.40-2.75 (m, 2H), 2.45 (s, 3H), 2.80-3.10 (AB part of an ABX, 2H, JAX=4.4, JBX=7.5, JAB=12.5 Hz),
4.30-4.55 (m, 2H), 5.50 (X part of an ABX, 1H, JAX=4.4, JBX=7.5), 6.95-8.00 (m, 9H); 13C NMR (CDCl3)
δ/TMS 21.4, 34.0, 37.4, 65.7, 68.8, 82.3, 114.9-149.0, 174.6, 194.8; Anal. Calcd for C20H19NO4: C,
71.20; H, 5.68; N, 4.15. Found: C, 70.97; H, 5.76; N, 4.21.
3’-(4-Methoxybenzoyl)-2’-phenyl-2’,3’-dihydrospiroisoxazolino[5’:3]dihydro-(3H)-furan-2-one (19c)
Colorless solid; yield 0.58 g (33%); mp 136-138 °C; IR (KBr) 1775, 1680 cm-1; 1H NMR (CDCl3) δ/TMS
2.35-2.75 (m, 2H), 2.85-3.05 (AB part of an ABX, 2H, JAX=4.5, JBX=7.0, JAB=12.4 Hz), 3.95 (s, 3H),
4.30-4.55 (m, 2H), 5.45 (X part of an ABX, 1H, JAX=4.5, JBX=7.0), 6.90-8.15 (m, 9H); 13C NMR (CDCl3)
δ/TMS 34.3, 37.2, 56.4, 65.9, 69.0, 82.6, 110.9-160.0, 174.7, 193.0; Anal. Calcd for C20H19NO5: C,
67.98; H, 5.42; N, 3.96. Found: C, 68.13; H, 5.51; N, 3.89.
3’-(4-Nitrobenzoyl)-2’-phenyl-2’,3’-dihydrospiroisoxazolino[5’:3]dihydro-(3H)-furan-2-one (19d)
1
Yellow solid; yield 0.77 g (42%); mp 180-181 °C, IR (KBr) 1775, 1700 cm-1, H NMR (acetone-d6)
δ/TMS 2.40-2.80 (m, 2H), 2.80-3.20 (AB part of an ABX, 2H, JAX=7.1, JBX=2.9, JAB=12.7 Hz), 4.30-4.55
13
(m, 2H), 5.95 (X part of an ABX, 1H, JAX=7.1, JBX=2.9), 6.90-8.50 (m, 9H); C NMR (acetone-d6)
δ/TMS 35.1, 37.0, 66.6, 70.3, 84.2, 115.7-151.2, 175.4, 196.6; Anal. Calcd for C19H16N2O6: C, 61.95; H,
4.38; N, 7.61. Found: C, 62.14; H, 4.33; N, 7.67.
3’-Benzoyl-2’-phenyl-2’,3’-dihydrospiroisoxazolino[5’:3]succinic anhydride (20a)

HETEROCYCLES, Vol. 78, No. 8, 2009
1989
1
White solid; yield 1.55 g (92%); mp 135-136 °C; IR (KBr) 1875, 1795, 1680 cm-1; H NMR (CDCl3)
δ/TMS 2.95-3.20 (AB part of an ABX, 2H, JAX=6.7, JBX=2.6, JAB=12.7 Hz), 3.20-3.55 (AB, 2H,
13
JAB=19.6 Hz), 5.65 (X part of an ABX, 1H, JAX=6.7, JBX=2.6), 7.00-8.10 (m, 10H); C NMR (CDCl3)
δ/TMS 37.6, 41.0, 68.1, 84.4, 115.4-147.7, 166.7, 170.7, 194.4; Anal. Calcd for C19H15NO5: C, 67.65; H,
4.48; N, 4.15. Found: C, 67.93; H, 4.52; N, 4.13.
3’-(4-Methylbenzoyl)-2’-phenyl-2’,3’-dihydrospiroisoxazolino[5’:3]succinic anhydride (20b)
1
White solid; yield 1.36 g (77%); mp 133-134 °C; IR (KBr) 1875, 1790, 1680 cm-1; H NMR (CDCl3)
δ/TMS 2.45 (s, 3H), 2.95-3.15 (AB part of an ABX, 2H, JAX=6.5, JBX=2.7, JAB=12.8 Hz), 3.15-3.55 (AB,
2H, JAB=19.5 Hz), 5.65 (X part of an ABX, 1H, JAX=6.5, JBX=2.7), 7.00-8.00 (m, 9H); 13C NMR (CDCl3)
δ/TMS 21.6, 37.8, 40.9, 68.1, 84.3, 115.4-147.8, 166.9, 170.9, 194.1; Anal. Calcd for C20H17NO5: C,
68.37; H, 4.88; N, 3.99. Found: C, 68.59; H, 4.97; N, 4.03.
3’-(4-Methoxybenzoyl)-2’-phenyl-2’,3’-dihydrospiroisoxazolino[5’:3]succinic anhydride (20c)
1
White solid; yield 1.45 g (79%); mp 132-133 °C; IR (KBr) 1880, 1805, 1680 cm-1; H NMR (CDCl3)
δ/TMS 2.95-3.20 (AB part of an ABX, 2H, JAX=6.8, JBX=2.5, JAB=12.5 Hz), 3.20-3.55 (AB, 2H,
JAB=19.5 Hz), 3.90 (s, 3H), 5.60 (X part of an ABX, 1H, JAX=6.8, JBX=2.5), 6.80-8.10 (m, 9H); 13C NMR
(CDCl3) δ/TMS 37.8, 40.9, 55.4, 67.9, 84.3, 113.9-164.1, 166.9, 170.9, 192.8; Anal. Calcd for
C20H17NO6: C, 65.39; H, 4.66; N, 3.81. Found: C, 65.15; H, 4.81; N, 4.01.
3’-(4-Nitrobenzoyl)-2’-phenyl-2’,3’-dihydrospiroisoxazolino[5’:3]succinic anhydride (20d)
1
Yellow solid; yield 1.71 g (90%); mp 148-150 °C; IR (KBr) 1875, 1790, 1680 cm-1; H NMR (CDCl3)
δ/TMS 2.95-3.20 (AB part of an ABX, 2H, JAX=6.7, JBX=1.6, JAB=12.8 Hz), 3.15-3.55 (AB, 2H,
13
JAB=19.5 Hz), 5.70 (X part of an ABX, 1H, JAX=6.7, JBX=1.6), 7.00-8.40 (m, 9H); C NMR (CDCl3)
δ/TMS 37.2, 41.0, 68.7, 84.7, 115.7-147.5, 166.2, 170.4, 193.6; Anal. Calcd for C19H14N2O7: C, 59.69; H,
3.69; N, 7.33. Found: C, 59.42; H, 3.81; N, 7.16.
X-Ray crystal structure analyses of compounds (19d) and (20d)
For both structures, data were measured from very small prismatic crystals with a Nonius Kappa-CCD
area-detector diffractometer, using graphite monochromated Mo-Kα radiation, according to the phi and
omega scan method, up to θ = 19° for (19d) and 22° for (20d).40 The structures were solved with program
SHELXS8641 and refined by full-matrix least-squares, based upon all unique F2 with program
SHELXL97.42 The hydrogen atoms were fitted at theoretical positions and treated as riding, assigned of an
isotropic displacement parameter equivalent to 1.10 the one of the bonded atom. CCDC 664441 &
664442 contain the supplementary crystallographic data for (19d) and (20d) respectively. These data can
be obtained free of charge from the Cambridge Crystallographic Data Center via
www.ccdc.cam.ac.uk/data_request/cif.

1990
HETEROCYCLES, Vol. 78, No. 8, 2009
ACKNOWLEGDEMENTS
We thank Gregorio Crini (CERAC, University of Franche-Comté) for NMR measurements, E. Pousson
(University of Bourgogne) for performing the elemental analyses, and Angèle Chiaroni (Laboratory of
Crystallochemistry, Institute of Chemistry of Natural Products) for fruitful collaboration on X-ray studies.
Sandrine Gerber (Laboratory of Glycochemistry and Asymetric Synthesis, Institute of Chemical Science
and Engineering) is also acknowledged for fruitful discussion. This work was supported by the French
Ministry of Research.
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