Spiroheterocycles from reaction of nitrones with methylene-γ-butyrolactones and some of their rearrangements

Article abstract of DOI:10.1039/b300628j

Cycloaddition of nitrones 1 with methylene-γ-butyrolactones 2, 3 and 4 afforded spiroadducts 5, 6 and 7 with high selectivity. Mixtures of diastereoisomers were usually obtained, whose structures were established by ¹H and ¹³C NMR spectroscopies or X-ray crystallography. Treatment of spiroadducts in acidic and alkaline media led to different, unexpected and novel rearrangements.

Full text of DOI:10.1039/b300628j

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Spiroheterocycles from reaction of nitrones with
methylene-ꢀ-butyrolactones and some of their rearrangements
Christophe Roussel,†a Rachid Fihi,b Kabula Ciamala,*a Joël Vebrel,a Touria Zairc and
Claude Riched
a Laboratoire de Chimie des Matériaux et Interfaces, UFR Sciences et Techniques,
16 Route de Gray, F-25030 BESANCON Cedex, France
b Laboratoire des Substances Naturelles-Synthèse et Dynamique Moléculaire,
Faculté des Sciences et des Techniques, BP 509, ERRACHIDIA-Maroc
c Laboratoire de Chimie Organique Appliquée, Faculté des Sciences, BP 4010,
Beni M’hamed MEKNES-Maroc
d Laboratoire de Cristallochimie, Institut de Chimie des Substances Naturelles-CNRS,
Avenue de la Terrasse, F-91198 GIF SUR YVETTE Cedex, France
Received 22nd January 2003, Accepted 6th June 2003
First published as an Advance Article on the web 30th June 2003
Cycloaddition of nitrones 1 with methylene-γ-butyrolactones 2, 3 and 4 afforded spiroadducts 5, 6 and 7 with high
selectivity. Mixtures of diastereoisomers were usually obtained, whose structures were established by 1H and 13
NMR spectroscopies or X-ray crystallography. Treatment of spiroadducts in acidic and alkaline media led to
different, unexpected and novel rearrangements.
C
with resonance stabilised methylene-butyrolactones such as
3-methylenephthalide 3 and protoanemonin 4. As a result of
these reinvestigations, we present here the first examples where
C-aroyl-N-phenylnitrones 1b–e reacted with methylene-γ-
butyrolactones. Finally, acid or base-promoted rearrangement
of some cycloadducts is described.
Introduction
Heterocyclic spirocompounds are of interest in synthetic
organic chemistry. Indeed, the presence of a spirocarbon atom
induces a relative steric strain and allows thermal, base or acid-
promoted rearrangement of these products, yielding new and
often unexpected heterocycles.1–8 The cycloaddition between
dipolarophiles bearing an exocyclic carbon–carbon double
bond and appropriate 1,3-dipoles is one of the best methods
for the synthesis of bicyclic spirocompounds. It was previ-
ously reported that 1,3-dipolar cycloaddition of aromatic
nitrile oxides with 3-methylenephthalide 3 produced 3Ј-aryl-
spiro[isobenzofuran-1(3H ),5Ј(4ЈH )-isoxazol]-3-ones.9,10 These
spiroheterocycles were readily converted to 2-(3-arylisoxazol-5-
yl)benzoate derivatives, which were of considerable interest in
the pharmaceutical industry and agronomics.11–15 The spiro-
heterocycles themselves possessed good herbicidal and plant
growth regulant activities.16
As part of our research on bicyclic spirocompounds, we
recently reported that methylene-γ-butyrolactones reacted with
arylnitrile oxides with high selectivity.2 The spiroadducts
obtained from 5-methylene(5H )furan-2-one (protoanemonin)
could be cleaved to the corresponding (2E)-3-(3Ј-arylisoxazol-
5Ј-yl)propenoic acids and 3-aryl-5[4Ј-(3Ј-aryl-4Ј,5Ј-dihydro-
isoxazolinyl)]isoxazoles in various ways, including acidic or
alkaline treatments and electrooxidation. The 1,3-dipolar
cycloaddition of 3,4-dihydro-2H-pyrrole-1-oxide (cyclic
nitrone) with α, β and γ-methylene-γ-butyrolactones has been
reported in the literature.17 Recently, Goti and co-workers18
have reported the reaction of the sole C,N-diphenylnitrone 1a
with α-methylene-γ-butyrolactone in refluxing benzene or tolu-
ene. The cycloaddition afforded two diastereomeric 5-spiro-
substituted isoxazolidines with high selectivity. In the same
reaction conditions, γ-methylene-γ-butyrolactone 2 led to
decomposition products. We first reinvestigated this last reac-
tion and our results were in disagreement with Goti’s. Our
study was then extended to the cycloaddition of nitrone 1a
Results and discussion
Firstly, we ran cycloadditions of nitrones 1 with methylene-γ-
butyrolactones 2–4 in refluxing toluene. The reactions pro-
ceeded repeatedly with low isolated yields because of the
concomitant polymerisation of these unstable dipolarophiles.
This phenomenon was clearly proven in a systematic study of
the thermal behaviour of methylene-γ-butyrolactones by differ-
ential thermal analysis. Thus, γ-methylene-γ-butyrolactone
had a propensity to polymerize readily. 3-Methylenephthalide
shows a good stability below 80 ЊC. After an endothermic peak
situated at 54 ЊC corresponding to the melting of the com-
pound, an exothermic reaction was observed above 80 ЊC.
Beyond this temperature, an exothermic peak (maximum situ-
ated at about 130 ЊC) attributed to the thermal polymerisation
of this methylene-lactone was observed. In the case of proto-
anemonin, an exothermic curve corresponding to a degrad-
ation process was observed at a temperature as low as 30 ЊC,
confirming the instability of this lactone previously described
by Shaw.19 Concerning nitrones, a degradation process occurred
after the melting point was reached. This phenomenon was
pointed out by the presence of an exothermic peak situated just
after the melting point. In the light of these results, we decided
to perform most reactions at room temperature. All cyclo-
additions generally gave a mixture of two diastereoisomers.
Pure stereoisomers coming from the [3ϩ2] cycloaddition were
then obtained after separation of the crude mixture by flash-
chromatography or by fractional crystallisation. Reaction tem-
perature and isolated non optimized yields are reported in the
experimental section and in Scheme 1.
In contrary to Goti’s results,18 we have succeeded in reacting
γ-butyrolactone 2 with nitrone 1a, without any formation of
degradation products.
† Present address: Laboratoire d’Electrochimie physique et Analytique,
Institut de Chimie Moléculaire et Biologique, Ecole Polytechnique
Fédérale de Lausanne, CH-1015 Lausanne (Switzerland).
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 6 8 9 – 2 6 9 8
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Scheme 1
Regiochemistry
1
The regiochemistry of 5, 6 and 7 can be deduced from H and
1
13C NMR spectra. In the H NMR spectra of 5, 6 and 7, the
signal of proton 3Ј-H appeared as a triplet or a doublet of
doublets around δ = 4.45–5.60 ppm. It was coupled with pro-
tons 4aЈ-H and 4bЈ-H. This excluded the presence of the inverse
regioisomer, in which the NMR spectrum would exhibit a
singlet for 3Ј-H and an AB system for the two hydrogen atoms
at the 5Ј-position of the isoxazolidine ring. This was confirmed
by the 13C chemical shift of the spirocarbon atoms of all
adducts (109–117 ppm), which was in accord with the presence
of two vicinal electronegative atoms (the oxygen of the lactone
ring and the oxygen of the isoxazolidine). The regiochemistry
thus observed was in agreement with previous results.17,20,21
Stereochemistry
The cycloaddition of methylene-γ-butyrolactones with nitrones
1 led to cycloadducts with two new chiral centres, i.e. the
quaternary spiroatom and the carbon bearing the ‘R’ substi-
tuent of the isoxazolidine ring. The relative ratios of stereo-
Fig. 1 X-ray crystal structure of 6Xd.
quality. X-ray structural analysis to elucidate its stereo-
chemistry, which resulted from the endo approach of the dipole
towards lactone carbonyl group (Fig. 1), was thus possible. The
examination of this structure revealed a cis relationship
1
isomers were evaluated by integration of 3Ј-H from H NMR
spectra of the crude reaction mixtures (relative accuracy 5%).
The formation of diastereoisomeric adducts was never caused
by any Z/E interconversion of nitrones,18,21,22 the relative
configuration (Z) of the dipole always being preserved in spiro-
compounds (Fig. 1, Scheme 1).
Only diastereoisomer 6Xd resulting from the cycloaddition
of 3-methylenephthalide with nitrone 1d gave crystals of good
between the proton 3Ј-H and C᎐O of the lactone ring.
᎐
For all adducts, the chemical shifts of each hydrogen atom
carried by the isoxazolidine moiety have been unambiguously
ascribed according to observations made in previous
reports.23,24,25 Indeed, it was clearly established that the values
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 6 8 9 – 2 6 9 8
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of the cis coupling constants were always larger than that of the
trans coupling constants. In addition, it has been shown that the
difference in chemical shifts of the two C-4 protons, can be used
to establish the relative stereochemistry of the C-3 and C-5
substituents.26
The two modes of approach (endo C᎐O and exo C᎐O) of the
᎐ ᎐
nitrones 1 towards dipolarophiles 2, 3 and 4 are depicted in
Scheme 2.
As pointed out by Goti and co-workers, using RHF/AM1
calculations for transition states, in the case of an endo C᎐O
᎐
Goti and co-workers have reacted C,N-diphenylnitrone
with α-methylene-γ-butyrolactone and obtained two diastereo-
isomeric adducts.18 The major spirocompound corresponded to
an endo approach of the reactants, locating 3Ј-H in a cis
position toward the lactone function; the non equivalent 4Ј-H
protons resonated at 2.56 and 3.12 ppm (∆δ = 0.56). In the
minor adduct, the same protons were located at 2.86 and 2.97
ppm (∆δ = 0.11). Such observations have been made for com-
pound 6Xd in which ∆δ was around 0.3 (3Ј-H was in a cis
configuration toward the lactone function). One could possibly
deduce that diastereoisomer 6Yd (∆δ = 0.10), which has the
opposite relative stereochemistry at C-3Ј and C-5Ј, is derived
approach, the carbonyl group facing the N-phenyl was corr-
ectly situated for
a stabilizing secondary orbital inter-
action, which might work in combination with steric effects
in determining the high stereoselectivity.18 Theoretical
calculations of two transition state structures gave a much
higher energy for the exo approach. On the other hand,
unfavorable steric interactions between the proton at C-4 of the
lactone pointing towards the nitrone and the N-phenyl group
of the nitrone in the exo C᎐O approach were observed. Accord-
᎐
ing to previously reported data and in agreement with the
FMO theory, the higher electronic density of the double
bond of protoanemonin 4 compared with other lactones,
makes γ-methylene-γ-butyrolactone less reactive towards
nitrones.17 Initial attempts at reacting nitrone 1a with γ-methyl-
ene-γ-butyrolactone led to decomposition products.18 When
the reaction was performed at room temperature in ethyl
acetate, starting materials were recovered. Nevertheless,
we succeeded in obtaining a mixture of diastereoisomers 5Xa
and 5Ya (50%, 3 : 2) by refluxing C,N-diphenylnitrone 1a with
γ-methylene-γ-butyrolactone 2 in ethyl acetate for 24 h. The
cycloaddition was not diastereoselective. As indicated by
molecular model studies, the distance between carbonyl
and N-phenyl groups on the one hand and N-phenyl and the
from the exo C᎐O approach.
᎐
Furthermore, taking the spectroscopic data of other adducts
into account, the observations described above could be gener-
alized for clarifying all structures coming from the cyclo-
addition of nitrones and dipolarophiles 2, 3 and 4. Concerning
compounds 5Xa, 6Xa and 7Xa, we noticed that the chemical
shifts of 4Јa-H and 4Јb-H were very close to those observed by
Goti. These remarks were even more patent for 5Ya and 6Ya.
For instance, in the case of 5Ya, chemical shifts of 4Ј-H were
located at 2.85 and 2.95 ppm, exactly as described in the
literature.18
Scheme 2
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 6 8 9 – 2 6 9 8
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isoxazolidinic ring on the other hand were significant. Con-
sequently, we assumed that approaches could be endo C᎐O
᎐
as well as exo C᎐O, which ultimately led to the two possible
᎐
stereoisomers with almost no selectivity. PM3 calculations
using the model compounds 5Xa and 5Ya gave no signifi-
cant differences between transition states energies of the two
diastereoisomers.
In contrast to the reaction of protoanemonin 4 with 3,4-di-
hydro-2H-pyrrole-1-oxide,17 the exocyclic double bond of this
lactone was more reactive than the endocyclic double bond
towards nitrones 1a and 1b–e. Therefore, no reaction occurred
at the endocyclic double bond when 4 was reacted with C,N-
diphenylnitrone: the crude mixture revealed only the presence
1
of diastereoisomer 7Xa (7Ya was not detected by H NMR).
We assigned the two doublets of doublets at 2.85 and 3.20 ppm
(∆δ = 0.35) to 4Јa-H and 4Јb-H and the doublet of doublets at
4.65 ppm to 3Ј-H. Assignment of structure 7Xa was straight-
forward on the basis of spectroscopic data, according to
observations from 6Xd.
The cycloaddition of nitrones 1b–e with protoanemonin 4
proceeded with high stereoselectivity (Scheme 1). The high
selectivity of the cycloaddition was evidenced by the presence
of conjugate double bonds in both compounds, as shown in 1H
and 13C NMR spectra (experimental section).
The structural elucidation of adducts 7Xb–e and 7Yb–e was
based on their spectroscopic data. The stereochemistry was
determined by two-dimensional NMR spectroscopy (NOESY
experiments) and comparison with 6Xd spectra.
Fig. 3 1H–1H NOESY spectrum of compound 7Xc.
Rearrangement of spiroadducts
Acidic treatment. Treatment of spiroadducts 6Xa and 6Ya –
either alone or in a mixture – with concentrated hydrochloric
acid gave a unique product 8a (Scheme 3).
The NOESY spectra in CDCl3 of diastereoisomers 7Xc
and 7Yc were carried out in order to establish any effective
correlation among protons. While no significant interaction
was evidenced in the NOESY spectrum of major diastereo-
isomer 7Yc, the spectrum of minor isomer 7Xc showed a
correlation between a proton (4Јa-H) of the isoxazolidine
ring and the proton 4-H of the lactone ring (Figs. 2
and 3).
The rearrangement did not stop after the simple opening of
the lactone ring: the elimination of phenylhydroxylamine led to
a functionalized chalcone. This result was in accordance with
literature reports.27–29
1
In the H NMR spectrum of compound 8a, the chemical
shift values showed that all protons were linked to sp2 carbon
a
b
atoms and the value of the coupling constant (JH –H
=
16.3 Hz) was in favour of the E stereochemistry. Further
information was obtained from the 13C NMR spectrum of
8a, in which all chemical shifts were above 120 ppm. The IR
spectra revealed the presence of two carbonyl functions (1690
and 1645 cmϪ1). The mass spectrum in the chemical ionisation
mode gave a molecular peak at m/z 253.
We conducted the same reaction with adducts 5a, 6b–e and
7a–e, but we noted a decomposition of the starting materials
(i.e. at room temperature as well as 0 ЊC using small amount of
HCl).
We propose here a mechanism for this ring opening reaction
(Scheme 4).
Alkaline treatment. Spiroadducts 5–7 were submitted to
alkaline treatment (ethanolic NaOH at room temperature).
Only decomposition of 5Xa and 5Ya was observed. Adducts
6Xa and 6Ya led to the previously obtained chalcone 8a
(Scheme 3). However, alkaline treatment of spiroheterocycles
6Xb–e and 6Yb–e (obtained by reaction of C-aroyl-N-
phenylnitrones 1b–e with 3-methylenephthalide 3) gave 2-(4-
aryl-1,4-dioxo-3-N-phenylaminobut-2-ene)benzoic acid 9b–e
(Scheme 3). We propose a mechanism for the two base
promoted rearrangements (Scheme 5).
In addition to the IR data (see experimental section), the
structure of the rearrangement products 9b–e was confirmed by
the presence of a single ethylenic proton at 5.70–5.90 ppm (s),
another singlet at 12.20–12.40 ppm (NH) and a large singlet at
8.00–9.00 ppm (OH).
Fig. 2 1H–1H NOESY spectrum of compound 7Yc.
This interaction revealed unfavorable electronic repulsion in
the transition state of the endo approach, leading to minor
adducts 7Xb–e. In this case, the 3Ј-H proton appeared cis with
The 13C NMR revealed the presence of two non aromatic sp2
carbon atoms and three carbonyl functions. The mass spectra in
the chemical ionisation mode gave a molecular peak at m/z: 386
(9c).
respect to the lactone C᎐O and trans to the 4-H proton. In the
᎐
absence of electronic repulsion and steric hindrance, the exo
approach was favoured. The 3Ј-H proton in the resulting major
products 7Yb–e was trans with respect to the lactone C᎐O and
When submitted to the same reaction conditions, the spiro-
heterocycles 7b–e (obtained by reaction of 5-methylene-
(5H )furan-2-one 4 with C-aroyl-N-phenylnitrones 1b–e) gave
᎐
cis to the 4-H proton.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 6 8 9 – 2 6 9 8
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Scheme 3
Scheme 4
2-(aroyl)-4-hydroxy-N-phenylpyrrole-5-acetic acids 10b–e
strong IR band was observed, assigned to the C᎐O of the carb-
oxylic acid and ketone. The mass spectrum of compound 10c
᎐
(Scheme 6).
1
Analytical and spectroscopic data (IR, H and 13C NMR)
1
was obtained by electron impact at
were in agreement with the assigned structures 10b–e. The H
NMR spectra of compounds 10b–e clearly indicated the pres-
ence of two protons (12.40–12.80 ppm and 8.75–8.95 ppm)
exchangeable with D2O. The singlet observed at 6.30–6.35 ppm
was assigned to the pyrrolic proton. Another singlet was
observed at 3.40 ppm, ascribable to the methylene group of the
acetic moiety. As expected, in the 13C NMR spectra of 10b–e,
the signals of the C-atoms were located at 29, 113–162, 170 and
181–184 ppm, assigned to the methyl group, aromatic, pyrrolic
70 eV (m/z = 335) and chemical ionisation (m/z = 336). A prob-
able mechanism for the rearrangement of adducts 7b–e is
described in Scheme 7.
Conclusion
We have studied the reactivity of methylene-γ-butyrolactones
2–4 towards acyclic nitrones 1. All spiroadducts were formed
via a very high regioselectivity pathway, the spirocarbon atom
being linked to the isoxazolidine oxygen atom. The stereo-
and C᎐O (COOH, ketone) carbons respectively. All the com-
᎐
pounds 10b–e, showed a large band at 3570–2840 cmϪ1, which is
typical of OH groups (acid and enol). At 1720–1700 cmϪ1
a
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 6 8 9 – 2 6 9 8
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Scheme 6
Experimental
General
Melting points were carried out on an Electrothermal IA 9200
instrument and are uncorrected. Differential thermal analyses
(DTA) were recorded on a Mettler DSC 20 apparatus using
5 mg of substance 1–4 between 30 and 200 ЊC, with a heating
rate of 10 K minϪ1. IR spectra (KBr) were recorded on a Bio-
Rad FTS-7 spectrophotometer. 1H and 13C NMR spectra were
recorded on a Bruker AC200 spectrometer [200 MHz (1H) and
50 MHz (13C)]. All compounds were dissolved in CDCl3, [d6]
DMSO or [d6] acetone with 0.1% TMS as an internal reference.
The 13C NMR spectra were obtained from proton-noise
decoupled spectra. Chemical shifts are in ppm on the δ scale
and coupling constants J are given in Hz. In 1H and 13C NMR
spectra, hydrogen and carbon atoms are numbered according to
the IUPAC nomenclature rules. All liquid chromatography was
performed in 2.5 cm inside diameter Pyrex columns packed
with Kieselgel 60, particle size 0.063–0.200 mm, from Merck
(art. 1.07734.1000). Preparative TLC was carried out on silica
gel plates 60 F254. Analytical data were obtained by the CNRS
(Vernaison, France) and were satisfactory (C, H, N within
0.30% of theoretical value). Mass spectra were recorded on a
NERMAG R 1010 H apparatus under electronic impact at
70 eV or by chemical ionisation. Yields are given for isolated
products.
The crystal data for product 6Xd is as follows: colourless
crystal (0.10 × 0.40 × 0.40 mm); empirical formula C24H19NO5;
formula weight 401.40; monoclinic, space group P21/c; Z = 4;
a = 9.726 (3) Å, b = 18.482 (5) Å, c = 11.049 (3) Å, β = 102.86
(3)Њ, u = 1936.3 Å3, dc = 1.377 g. cmϪ3, F(000) = 840, λ (CuKα) =
1.5418 Å, µ = 0.80 mmϪ1, 7262 data measured on a Nonius-
CAD4 diffractometer up to θmax = 68Њ (Ϫ11 ≤ h ≤ 11, Ϫ18 ≤ k ≤
22, 0 ≤ l ≤ 12) reduced to 3515 unique reflections (Rint = 0.043),
of which 2652 were considered as observed with I ≥ 2.0σ(I ).
Structure solved with program SHELXS8630 and refined with
program SHELXL93.31 Refinement converged to R1(F) =
0.0400 for the 2652 observed Fo and wR2 = 0.1188 for
all the 3515 data with goodness-of-fit S = 1.069. In the final
difference map, the residual electron density was found
between Ϫ0.18 and 0.42 e ÅϪ3. For further information see
ref. 32.
Scheme 5
selectivity of the reaction was explained by the possible elec-
tronic interactions or steric hindrance of reactants during their
approach in the transition states.
The cycloaddition of protoanemonin with C,N-diphenyl-
nitrone or C-aroyl-N-phenylnitrone showed a good diastereo-
selectivity, which was rationalized in terms of unfavorable
electronic repulsion, leading to the minor diastereoisomers.
In both cases, no reaction was observed on the endocyclic
double bonds. In the case of γ-methylene-γ-butyrolactone 2
and 3-methylenephthalide 3, the absence of these effects led
to the two possible stereoisomers with almost no stereo-
selectivity.
Treatment in acid and alkaline environments of the same
spiroadducts led to different compounds and gave rise to
unexpected and unprecedented rearrangement reactions.
Methylene-γ-lactones 2, 3, and 4,9,33,34 C-phenyl-N-phenyl-
nitrone35 1a and C-aroyl-N-phenylnitrone 1b–e36,37 were pre-
pared according to literature procedures.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 6 8 9 – 2 6 9 8
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Scheme 7
Cycloadducts 5a, 6a and 7a: general procedure
J = 9.6 Hz, 3Ј-H), 7.10–7.95 (14H, m, ArH ); δC 50.3 (C-4Ј), 70.5
(C-3Ј), 109.0 (C-5:5Ј), 116.2–138.5 (ArC), 167.5 (C᎐O, lactone).
᎐
A solution of nitrone 1a (1.97 g, 10 mmol), methylene-γ-butyro-
lactone 2, 3 or 4 (10 mmol) and 0.05 g of hydroquinone in ethyl
acetate (40 cm3) was stirred at 78 ЊC under a nitrogen
atmosphere. After the disappearance of the starting materials
(24 h), the solvent was removed. The residue was crystallized
(ethanol), affording a mixture of diastereoisomers as colourless
crystals. A sample of the diastereoisomeric mixture was
purified by chromatography on silica gel (eluent: chloroform–
hexane–ether, 50 : 25 : 25 (5a); chloroform–hexane–ether,
50 : 45 : 5 (6a)).
6Ya (0.51 g, 15%) as colourless solid mp 127–128 ЊC
(ethanol); Found: C, 77.1; H, 4.9; N, 4.3; C22H17NO3 requires C,
76.9; H, 4.9; N, 4.1%; νmax(KBr)/cmϪ1: 1770 ν (C᎐O, lactone);
᎐
δH 3.05 (1H, dd, J = 7.0 Hz, J = 12.8 Hz, 4Јa-H), 3.15 (1H, dd,
J = 10.3 Hz, J = 12.8 Hz, 4Јb-H), 5.10 (1H, dd, J = 7.0 Hz,
J = 10.3 Hz, 3Ј-H), 7.10–7.95 (14H, m, ArH ); δC 50.7 (C-4Ј),
70.3 (C-3Ј), 111.0 (C-5:5Ј), 116.5–139.1 (ArC), 167.0 (C᎐O,
᎐
lactone).
(3ЈR*;5,5ЈS*)-2Ј,3Ј-Diphenyl-2Ј,3Ј-dihydrospiroisoxazolino-
[5Ј:5]-(5H)-furan-2-one 7Xa. 7Xa (1.32 g, 45%) as colourless
solid mp: 162 ЊC (ethanol); Found: C, 73.9; H, 5.3; N, 5.1;
(3ЈR*;5,5ЈS*)-Spiro[tetrahydrofuran-2-one-5,5Ј-(2Ј,3Ј-di-
phenyl)tetrahydroisoxazole] 5Xa and (3ЈR*;5,5ЈR*)-spiro[tetra-
hydrofuran-2-one-5,5Ј-(2Ј,3Ј-diphenyl)tetrahydroisoxazole] 5Ya.
5Xa (0.88 g, 30%) as a colourless solid mp: 144 ЊC (ethanol);
Found: C, 72.9; H, 5.6; N, 4.7; C18H17NO3 requires C, 73.2; H,
5.8; N, 4.7%; νmax(KBr)/cmϪ1: 1770 (C᎐O, lactone); δ 2.70 (4H,
C18H15NO3 requires C, 73.7; H, 5.1; N, 4.8%; νmax(KBr)/cmϪ1
:
1770 ν (C᎐O, lactone), 1600 (C᎐C); δ 2.85 (1H, dd, J = 6.7 Hz,
᎐
᎐
H
J = 13.8 Hz, 4Јa-H), 3.20 (1H, dd, J = 9.3 Hz, J = 13.8 Hz, 4Јb-
H), 4.65 (1H, dd, J = 6.7 Hz, J = 9.3 Hz, 3Ј-H), 6.30 (d, 1H,
J = 5.5 Hz, 3-H), 7.20 (1H, d, J = 5.5, 4-H), 6.75–7.60 (10H, m,
ArH ); δC 47.8 (C-4Ј), 70.5 (C-3Ј), 110.2 (C-5:5Ј), 116.6–138.9
᎐
H
m, 3-H and 4-H), 3.05 (1H, dd, J = 6.9 Hz, J = 13.9 Hz, 4Јa-H),
3.40 (1H, dd, J = 9.6 Hz, J = 13.9 Hz, 4Јb-H) 4.85 (1H, dd,
J = 6.9 Hz, J = 9.6 Hz, 3Ј-H), 6.95–7.90 (10H, m, ArH ); δC 28.6
(C-4), 29.0 (C-4Ј), 49.9 (C-3), 69.4 (C-3Ј), 115.5 (C-5:5Ј), 116.5–
(ArC and C-3), 150.1 (C-4), 169.3 (C᎐O, lactone).
᎐
Cycloadducts 6b–e and 7b–e
139.5 (ArC), 166.3 (C᎐O, lactone).
᎐
5Ya (0.58 g, 20%) as colourless solid mp 136 ЊC (ethanol);
Found: C, 73.4; H, 5.8; N, 4.5; C18H17NO3 requires C, 73.2; H,
5.8; N, 4.7%; νmax(KBr)/cmϪ1: 1770 ν (C᎐O, lactone); δ 2.70
(4H, m, 3-H and 4-H), 2.85 (1H, dd, J = 6.7 Hz, J = 13.7 Hz,
4Јa-H), 2.95 (1H, dd, J = 9.8 Hz, J = 13.7 Hz, 4Јb-H), 4.45 (1H,
dd, J = 6.7 Hz, J = 9.8 Hz, 3Ј-H), 6.95–7.90 (10H, m, ArH );
δC 28.7 (C-4), 30.7 (C-4Ј), 50.0 (C-3), 69.5 (C-3Ј), 117.0 (C-5:5Ј),
To a solution of 10 mmol of methylene-γ-lactone and 0.05 g of
hydroquinone in 40 cm3 of ethyl acetate was added 10 mmol
of C-aroyl-N-phenylnitrone under a nitrogen atmosphere. The
reaction mixture was stirred at room temperature for 24 hours.
The solvent was removed and the residue was taken up in
ethanol and irradiated (triturated) by ultrasound. The solid
formed was filtered and separation of the diastereoisomers
was carried out by fractional crystallization from ethanol (6)
or by chromatography in pure dichloromethane (7). All the
compounds were recrystallised from ethanol.
᎐
H
116.9–139.8 (ArC), 166.4 (C᎐O, lactone).
᎐
(3ЈR*:5,5ЈS*)-2Ј,3Ј-Diphenyl-2Ј,3Ј-dihydrospiroisoxazolino-
[5Ј:5]-(3H)-isobenzofuran-2-one 6Xa and (3ЈR*;5,5ЈR*)-2Ј,3Ј-di-
phenyl-2Ј,3Ј-dihydrospiroisoxazolino[5Ј:5]-(3H)-isobenzofuran-
2-one 6Ya. 6Xa (1.20 g, 35%) as colourless solid mp: 150–151 ЊC
(ethanol); Found: C, 77.1; H, 5.0; N, 4.0; C22H17NO3 requires C,
(3ЈR*;5,5ЈS*)-3Ј-Benzoyl-2Ј-phenyl-2Ј,3Ј-dihydrospiroisox-
azolino[5Ј:5]-(3H)-isobenzofuran-2-one 6Xb and (3ЈR*;5,5ЈR*)-
3Ј-benzoyl-2Ј-phenyl-2Ј,3Ј-dihydrospiroisoxazolino[5Ј:5]-(3H)-
isobenzofuran-2-one 6Yb. 6Xb (1.20 g, 32%) as white solid mp:
145 ЊC (ethanol); Found: C, 74.5; H, 4.5; N, 3.7; C23H17NO4
76.9; H, 4.9; N, 4.1%; νmax(KBr)/cmϪ1: 1770 ν (C᎐O, lactone);
᎐
δH 3.05 (1H, dd, J = 6.9 Hz, J = 13.9 Hz, 4Јa-H), 3.40 (1H,
dd, J = 9.6 Hz, J = 13.9 Hz, 4Јb-H), 4.75 (1H, dd, J = 6.9 Hz,
requires C, 74.4; H, 4.6; N, 3.7%; νmax(KBr)/cmϪ1: 1765 ν (C᎐O,
᎐
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 6 8 9 – 2 6 9 8
2695

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lactone), 1680 (C᎐O aroyl); δ 3.20 (1H, dd, J = 7.4 Hz,
112.5 (C-5:5Ј), 115.8–150.4 (ArC), 166.5 (C᎐O, lactone), 194.1
᎐
᎐
H
J = 13.2 Hz, 4Јa-H or 4Јb-H), 3.45 (1H, dd, J = 7.4 Hz,
J = 13.2 Hz, 4Јa-H or 4Јb-H), 5.60 (1H, t, J = 7.4 Hz, 3Ј-H),
6.95–8.25 (14H, m, ArH ); δC 43.7 (C-4Ј), 69.2 (C-3Ј), 112.1
(C-5:5Ј), 115.9–150.0 (ArC), 166.8 (C᎐O, lactone), 194.9 (C᎐O,
(C᎐O, aroyl).
᎐
6Ye (2.03 g, 49%) as yellow solid mp: 156–157 ЊC (ethanol);
Found: C, 66.5; H, 3.9; N, 6.8; C23H16N2O6 requires C, 66.3; H,
3.8; N, 6.7%; νmax(KBr)/cmϪ1: 1780 ν (C᎐O, lactone), 1680
᎐
᎐
᎐
aroyl).
(C᎐O, aroyl); δH 3.25 (1H, dd, J = 9.3 Hz, J = 13.8 Hz, 4Јb-H),
᎐
6Yb (0.80 g, 22%) as white solid mp: 163–164 ЊC (ethanol);
Found: C, 74.6; H, 4.3; N, 3.5; C23H17NO4 requires C, 74.4; H,
4.6; N, 3.7%; νmax(KBr)/cmϪ1: 1770 ν (C᎐O, lactone) 1680 (C᎐O,
3.40 (1H, dd, J = 4.6 Hz, J = 13.8 Hz, 4Јa-H), 5.05 (1H, dd,
J = 4.6 Hz, J = 9.3 Hz, 3Ј-H), 7.00–8.60 (13H, m, ArH ); δC 43.5
(C-4Ј), 73.3 (C-3Ј), 110.1 (C-5:5Ј), 116.0–148.5 (ArC), 166.4
᎐
᎐
aroyl); δH 3.30 (1H, dd, J = 9.4 Hz, J = 14.0 Hz, 4Јb-H),
3.40 (1H, dd, J = 6.7 Hz, J = 14.0 Hz, 4Јa-H), 5.10 (1H, dd,
J = 6.7 Hz, J = 9.4 Hz, 3Ј-H), 7.00–8.35 (14 H, m, ArH ); δC 44.3
(C-4Ј), 72.5 (C-3Ј), 109.7 (C-5;5Ј), 116.4–148.7 (ArC), 166.8
(C᎐O, lactone), 195.8 (C᎐O, aroyl).
᎐ ᎐
(3ЈR*;5,5ЈS*)-3Ј-Benzoyl-2-phenyl-2Ј,3Ј-dihydrospiroisoxazol-
ino[5Ј:5]-(5H)-furan-2-one 7Xb and (3ЈR*;5,5ЈR*)-3Ј-benzoyl-
2-phenyl-2Ј,3Ј-dihydrospiroisoxazolino[5Ј:5]-(5H)-furan-2-one
7Yb. 7Xb (0.23 g, 7%) as colourless solid mp: 175–177 ЊC
(ethanol); Found: C, 70.7; H, 4.5; N, 4.1; C19H15NO4 requires C,
(C᎐O, lactone), 194.9 (C᎐O, aroyl).
᎐
᎐
(3ЈR*;5,5ЈS*)-3Ј-(4-Methylbenzoyl)-2Ј-phenyl-2Ј,3Ј-dihydro-
spiroisoxazolino[5Ј:5]-(3H)-isobenzofuran-2-one 6Xc and (3ЈR*;
5,5ЈR*)-3Ј-(4-methylbenzoyl)-2Ј-phenyl-2Ј,3Ј-dihydrospiroisox-
azolino[5Ј:5]-(3H)-isobenzofuran-2-one 6Yc. 6Xc (1.81 g, 47%)
as white solid mp: 151–152 ЊC (ethanol); Found: C, 75.0; H, 5.1;
N, 3.5; C24H19NO4 requires C, 74.8; H, 4.9; N, 3.6%; νmax(KBr)/
cmϪ1: 1760 ν (C᎐O, lactone), 1680 (C᎐O aroyl); δH 2.45 (3H, s,
71.0; H, 4.7; N, 4.3%; νmax(KBr)/cmϪ1: 1790 ν (C᎐O, lactone),
᎐
1685 (C᎐O, aroyl), 1595 (C᎐C); δ 2.80 (1H, dd, J = 6.7 Hz,
᎐
᎐
H
J = 13.3 Hz, 4Јb-H), 3.20 (1H, dd, J = 5.1 Hz, J = 13.3 Hz,
4Јa-H), 5.45 (1H, dd, J = 5.1 Hz, J = 6.7 Hz, 3Ј-H), 6.20 (1H, d,
J = 5.4 Hz, 3-H), 7.05 (d, 1H, J = 5.4 Hz, 4-H), 6.85–8.10 (10H,
m, ArH ); δC 39.6 (C-4Ј), 68.9 (C-3Ј), 113.8 (C-5:5Ј), 115.8–149.3
᎐
᎐
CH3), 3.15 (1H, dd, J = 7.5 Hz, J = 13.3 Hz, 4Јa-H or 4Јb-H),
3.45 (1H, dd, J = 7.5 Hz, J = 13.3 Hz, 4Јa-H or 4Јb-H), 5.55 (1H,
t, J = 7.5 Hz, 3Ј-H), 7.00–8.10 (13H, m, ArH ); δC 21.6 (CH3),
43.9 (C-4Ј), 69.1 (C-3Ј), 112.0 (C-5:5Ј), 115.7–150.1 (ArC),
166.9 (C᎐O, lactone), 194.4 (C᎐O, aroyl).
(ArC and C-3), 150.0 (C-4), 169.1 (C᎐O, lactone), 194.6 (C᎐O,
aroyl).
7Yb (0.94 g, 30%); as white solid mp: 83–85 ЊC (ethanol);
᎐ ᎐
Found: C, 71.3; H, 4.7; N, 4.2; C19H15NO4 requires C, 71.0; H,
4.7; N, 4.3%; νmax(KBr)/cmϪ1: 1785 ν (C᎐O, lactone), 1685
᎐
᎐
᎐
6Yc (0.97 g, 25%) as white solid mp: 164–165 ЊC (ethanol);
(C᎐O, aroyl), 1595 (C᎐C); δ 3.00 (1H, dd, J = 9.1 Hz,
᎐ ᎐
H
Found: C, 74.6; H, 5.0; N, 3.4; C24H19NO4 requires C, 74.8; H,
J = 13.7 Hz, 4Јb-H), 3.10 (1H, dd, J = 5.4 Hz, J = 13.7 Hz,
4Јa-H), 4.95 (1H, dd, J = 5.4 Hz, J = 9.1 Hz, 3Ј-H), 6.20 (1H, d,
J = 5.4 Hz, 3-H), 7.10 (d, 1H, J = 5.4 Hz, 4-H), 6.80–8.20 (10H,
m, ArH ); δC 41.2 (C-4Ј), 72.0 (C-3Ј), 110.8 (C-5:5Ј), 116.1–148.7
4.9; N, 3.6%; νmax(KBr)/cmϪ1: 1775 ν (C᎐O, lactone), 1680
᎐
(C᎐O, aroyl); δ 2.45 (3H, s, CH3), 3.30 (1H, dd, J = 9.3 Hz,
᎐
H
J = 13.7 Hz, 4Јb-H), 3.40 (1H, dd, J = 6.9 Hz, J = 13.7 Hz,
4Јa-H), 5.00 (1H, dd, J = 6.9 Hz, J = 9.3 Hz, 3Ј-H), 6.95–8.25
(13H, m, ArH ); δC 21.4 (CH3), 44.3 (C-4Ј), 72.1 (C-3Ј), 109.6
(ArC and C-3), 149.4 (C-4), 168.6 (C᎐O, lactone), 194.5 (C᎐O,
᎐
᎐
aroyl).
(C-5:5Ј), 116.3–148.7 (ArC), 166.8 (C᎐O, lactone), 194.1 (C᎐O,
᎐
᎐
aroyl).
(3ЈR*;5,5ЈS*)-3Ј-(4-Methylbenzoyl)-2Ј-phenyl-2Ј,3Ј-dihydro-
spiroisoxazolino[5Ј:5]-(5H)-furan-2-one 7Xc and (3ЈR*;5,5ЈR*)-
3Ј-(4-methylbenzoyl)-2Ј-phenyl-2Ј,3Ј-dihydrospiroisoxazolino-
[5Ј:5]-(5H)-furan-2-one 7Yc. 7Xc (0.39 g, 12%) as colourless
solid mp: 126 ЊC (ethanol); Found: C, 71.3; H, 4.9; N, 3.9;
(3ЈR*;5,5ЈS*)-3Ј-(4-Methoxybenzoyl)-2Ј-phenyl-2Ј,3Ј-di-
hydrospiroisoxazolino[5Ј:5]-(3H)-isobenzofuran-2-one 6Xd and
(3ЈR*;5,5ЈR*)-3Ј-(4-methoxybenzoyl)-2Ј-phenyl-2Ј,3Ј-dihydro-
spiroisoxazolino[5Ј:5]-(3H)-isobenzofuran-2-one 6Yd. 6Xd (0.91
g, 23%) as white solid mp: 152–153 ЊC (ethanol); Found: C,
71.6; H, 4.6; N, 3.5; C24H19NO5 requires C, 71.8; H, 4.7; N,
3.5%; νmax(KBr)/cmϪ1: 1760 ν (C᎐O, lactone), 1680 (C᎐O,
aroyl); δH 3.15 (1H, dd, J = 7.5 Hz, J = 13.2 Hz, 4Јa-H or 4Јb-
H), 3.45 (1H, dd, J = 7.5 Hz, J = 13.2 Hz, 4Јa-H or 4Јb-H), 3.90
(3H, s, OCH3), 5.55 (1H, t, J = 7.5 Hz, 3Ј-H), 6.90–8.20 (13H,
m, ArH ); δC 43.9 (C-4Ј), 55.4 (OCH3), 68.9 (C-3Ј), 112.0
C20H17NO4 requires C, 71.6; H, 5.1; N, 4.2%; νmax(KBr)/cmϪ1
:
1770 ν (C᎐O, lactone), 1695 (C᎐O, aroyl), 1605 (C᎐C); δ 2.45
᎐
᎐
᎐
H
(3H, s, CH3), 2.90 (1H, dd, J = 6.9 Hz, J = 13.2 Hz, 4Јb-H),
3.25 (1H, dd, J = 5.4 Hz, J = 13.2 Hz, 4Јa-H), 5.55 (1H, dd,
J = 5.4 Hz, J = 6.9 Hz, 3Ј-H), 6.30 (1H, d, J = 5.5 Hz, 3-H), 7.40
(d, 1H, J = 5.5 Hz, 4-H), 7.00–8.20 (9H, m, ArH ); δC 21.6
(CH3), 39.9 (C-4Ј), 68.8 (C-3Ј), 113.7 (C-5:5Ј), 115.7–149.4
᎐
᎐
(ArC and C-3), 150.0 (C-4), 169.1 (C᎐O, lactone), 194.1 (C᎐O,
᎐
᎐
(C-5:5Ј), 113.9–164.1 (ArC), 166.9 (C᎐O, lactone), 193.2 (C᎐O,
aroyl).
᎐
᎐
aroyl).
7Yc (1.55 g, 46%) as white solid mp: 148–149 ЊC (ethanol);
6Yd (1.37 g, 34%) as white solid mp: 161–162 ЊC (ethanol);
Found: C, 71.5; H, 5.2; N, 4.2; C20H17NO4 requires C, 71.6; H,
Found: C, 72.1; H, 4.7; N, 3.4; C24H19NO5 requires C, 71.8; H,
5.1; N, 4.2%; νmax(KBr)/cmϪ1: 1770 ν (C᎐O, lactone), 1695
᎐
4.7; N, 3.5%; νmax(KBr)/cmϪ1: 1770 ν (C᎐O, lactone), 1680
(C᎐O, aroyl), 1605 (C᎐C); δ 2.45 (3H, s, CH3), 3.05 (1H, dd,
᎐
᎐
᎐
H
(C᎐O, aroyl); δH 3.30 (1H, dd, J = 9.5 Hz, J = 13.9 Hz, 4Јb-H),
J = 8.6 Hz, J = 13.6 Hz, 4Јb-H), 3.15 (1H, dd, J = 6.1 Hz,
J = 13.6 Hz, 4Јa-H), 4.95 (1H, dd, J = 6.1 Hz, J = 8.6 Hz, 3Ј-H),
6.25 (1H, d, J = 5.3 Hz, 3-H), 7.20 (1H, d, J = 5.3 Hz, 4-H),
6.95–8.20 (9H, m, ArH ); δC 21.5 (CH3), 41.4 (C-4Ј), 71.7 (C-3Ј),
110.7 (C-5:5Ј), 116.1–148.7 (ArC and C-3), 149.5 (C-4), 168.7
᎐
3.40 (1H, dd, J = 7.3 Hz, J = 13.9 Hz, 4Јa-H), 3.90 (3H, s,
OCH3), 4.95 (1H, dd, J = 7.3 Hz, J = 9.5 Hz, 3Ј-H), 6.90–8.40
(13H, m, ArH ); δC 45.2 (C-4Ј), 55.3 (OCH3), 73.4 (C-3Ј), 109.6
(C-5:5Ј), 113.9–164.0 (ArC), 166.8 (C᎐O, lactone), 193.4 (C᎐O,
᎐
᎐
aroyl).
(C᎐O, lactone), 193.9 (C᎐O, aroyl).
᎐ ᎐
(3ЈR*;5,5ЈS*)-3Ј-(4-Nitrobenzoyl)-2Ј-phenyl-2Ј,3Ј-dihydro-
spiroisoxazolino[5Ј:5]-(3H)-isobenzofuran-2-one 6Xe and (3ЈR*;
5,5ЈR*)-3Ј-(4-nitrobenzoyl)-2Ј-phenyl-2Ј,3Ј-dihydrospiroisoxazol-
ino[5Ј:5]-(3H)-isobenzofuran-2-one 6Ye. 6Xe (0.87 g, 21%) as
yellow solid mp: 153–154 ЊC (ethanol); Found: C, 66.5; H, 3.8;
N, 6.9; C23H16N2O6 requires C, 66.3; H, 3.8; N, 6.7%; νmax(KBr)/
cmϪ1: 1780 ν (C᎐O, lactone), 1680 (C᎐O, aroyl); δ 3.20 (1H,
(3ЈR*;5,5ЈS*)-3Ј-(4-Methoxybenzoyl)-2Ј-phenyl-2Ј,3Ј-dihydro-
spiroisoxazolino[5Ј:5]-(5H)-furan-2-one 7Xd and (3ЈR*;5,5ЈR*)-
3Ј-(4-methoxybenzoyl)-2Ј-phenyl-2Ј,3Ј-dihydrospiroisoxazolino-
[5Ј:5]-(5H)-furan-2-one 7Yd. 7Xd (0.17 g, 5%) as colourless
solid mp: 164–165 ЊC (ethanol); Found: C, 68.7; H, 4.5; N, 4.2;
C20H17NO5 requires C, 68.4; H, 4.8; N, 4.0%; νmax(KBr)/cmϪ1
:
1780 ν (C᎐O, lactone), 1680 (C᎐O, aroyl), 1600 (C᎐C); δ 2.90
᎐
᎐
᎐
᎐
᎐
H
H
dd, J = 6.6 Hz, J = 13.5 Hz, 4Јa-H or 4Јb-H), 3.60 (1H, dd,
J = 6.6 Hz, J = 13.5 Hz, 4Јa-H or 4Јb-H), 5.60 (1H, t, J = 6.6 Hz,
3Ј-H), 7.00–8.40 (13H, m, ArH ); δC 42.1 (C-4Ј), 69.3 (C-3Ј),
(1H, dd, J = 6.8 Hz, J = 13.1 Hz, 4Јb-H), 3.30 (1H, dd,
J = 5.4 Hz, J = 13.1 Hz, 4Јa-H), 3.90 (3H, s, OCH3), 5.50 (1H,
dd, J = 5.4 Hz, J = 6.8 Hz, 3Ј-H), 6.30 (1H, d, J = 5.5 Hz, 3-H),
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 6 8 9 – 2 6 9 8
2696

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7.40 (1H, d, J = 5.5 Hz, 4-H), 6.90–8.20 (9H, m, ArH ); δC 40.0
(C-4Ј), 55.4 (OCH3), 68.7 (C-3Ј), 113.9 (C-5:5Ј), 113.9–164.1
(1H, s, NH); δC 21.6 (CH ), 97.3 (HC᎐), 122.1–145.6 (ArC),
᎐
3
157.9 (C᎐), 170.8 (C᎐O, acid), 190.9 (C᎐O, aroyl), 194.1 (C᎐O,
᎐
᎐
᎐
᎐
(ArC and C-3), 150.0 (C-4), 169.1 (C᎐O, lactone), 192.9 (C᎐O,
aroyl).
᎐
᎐
aroyl).
2-[4-(4-Methoxyphenyl)-1,4-dioxo-3-N-phenylaminobut-2-ene]-
benzoic acid 9d. 9d (98 mg, 98%) as yellow solid mp: 165–167 ЊC
(methanol); Found: C, 71.9; H, 4.9; N, 3.6; C24H19NO5 requires
C, 71.8; H, 4.7; N, 3.5%; νmax(KBr)/cmϪ1: 3130–2735 ν (OH
and NH), 1690 (C᎐O, acid), 1675 (C᎐O, aroyl); δ 3.90 (3H, s,
7Yd (1.01 g, 29%) as brown solid mp: 162–163 ЊC (ethanol);
Found: C, 68.7; H, 5.0; N, 3.8; C20H17NO5 requires C, 68.4; H,
4.8; N, 4.0%; νmax(KBr)/cmϪ1: 1780 ν (C᎐O, lactone), 1675
᎐
(C᎐O, aroyl), 1605 (C᎐C); δH 3.10 (1H, dd, J = 9.0 Hz, J = 13.7
᎐
᎐
Hz, 4Јb-H), 3.20 (1H, dd, J = 6.4 Hz, J = 13.7 Hz, 4Јa-H), 3.90
(3H, s, OCH3), 4.90 (1H, dd, J = 6.4 Hz, J = 9.0 Hz, 3Ј-H), 6.25
(1H, d, J = 5.5 Hz, 3-H), 7.25 (1H, d, J = 5.5 Hz, 4-H), 6.85–8.35
(9H, m, ArH ); δC 41.9 (C-4Ј), 55.3 (OCH3), 72.3 (C-3Ј), 110.6
᎐
᎐
H
OCH3), 5.85 (1H, s, ethylenic), 6.90–8.30 (14H, m, ArH and
OH), 12.40 (1H, s, NH); δ 55.4 (O–CH ), 97.0 (HC᎐), 114.1–
᎐
C
3
164.7 (ArC), 158.8 (C᎐), 170.0 (C᎐O, acid), 189.5 (C᎐O, aroyl),
᎐
᎐
᎐
193.9 (C᎐O, aroyl).
(C-5:5Ј), 113.8–163.9 (ArC and C-3), 149.4 (C-4), 168.8 (C᎐O,
᎐
᎐
lactone), 192.9 (C᎐O, aroyl).
᎐
2-[4-(4-Nitrophenyl)-1,4-dioxo-3-N-phenylaminobut-2-ene]-
benzoic acid 9e. 9e (96 mg, 92%) as yellow solid mp: 186–188 ЊC
(methanol); Found: C, 66.2; H, 3.8; N, 6.7; C23H16N2O6 requires
C, 66.3; H, 3.8; N, 6.7%; νmax(KBr)/cmϪ1: 3155–2735 ν (OH and
(3ЈR*;5,5ЈR*)-3Ј-(4-Nitrobenzoyl)-2Ј-phenyl-2Ј,3Ј-dihydro-
spiroisoxazolino[5Ј:5]-(5H)-furan-2-one 7Ye. 7Ye (1.90 g, 52%)
as orange solid mp: 136–138 ЊC (ethanol); Found: C, 62.1; H,
4.0; N, 7.5; C19H14N2O6 requires C, 62.3; H, 3.8; N, 7.6%;
νmax(KBr)/cmϪ1: 1780 ν (C᎐O, lactone), 1710 (C᎐O, aroyl),
NH), 1685 (C᎐O, acid), 1670 (C᎐O, aroyl); δ ([d ] acetone) 5.90
᎐
᎐
H
6
(1H, s, ethylenic), 7.00–8.60 (14H, m, ArH and OH), 12.30 (1H,
᎐
᎐
1595 (C᎐C); δ 3.00 (1H, dd, J = 9.0 Hz, J = 13.6 Hz, 4Јb-H),
s, NH); δ ([d ] acetone) 100.9 (HC᎐), 123.5–149.8 (ArC), 160.1
᎐
H
᎐
C
6
3.25 (1H, dd, J = 3.6 Hz, J = 13.6 Hz, 4Јa-H), 5.00 (1H, dd,
J = 3.6 Hz, J = 9.0 Hz, 3Ј-H), 6.30 (1H, d, J = 5.5 Hz, 3-H),
7.20 (1H, d, J = 5.5 Hz, 4-H), 6.90–8.55 (9H, m, ArH ); δC 40.6
(C-4Ј), 72.9 (C-3Ј), 111.2 (C-5:5Ј), 115.9–148.5 (ArC and C-3),
(C᎐), 173.6 (C᎐O, acid), 193.8 (C᎐O, aroyl), 199.6 (C᎐O, aroyl).
᎐
᎐
᎐
᎐
2-Benzoyl-4-hydroxy-N-phenylpyrrole-5-acetic acid 10b. 10b
(60 mg, 75%) as yellow solid mp: 165–166 ЊC (ethanol–H2O);
Found: C, 71.1; H, 4.8; N, 4.3; C19H15NO4 requires C, 71.0; H,
4.7; N, 4.3%; νmax(KBr)/cmϪ1: 3570–2840 ν (OH acid and enol),
149.1 (C-4), 168.1 (C᎐O, lactone), 195.3 (C᎐O, aroyl).
᎐
᎐
Acidic treatment of compounds 6Xa and 6Ya
1710 (C᎐O, acid and aroyl); δH ([d6] DMSO) 3.40 (2H, s, CH2),
᎐
6.30 (1H, s, 3-H), 7.05–7.95 (10H, m, ArH ), 8.80 (1H, s, OH),
12.40 (1H, s, OH); δC ([d6] DMSO) 29.0 (CH2), 110.2 (C-3),
122.1 (C-2), 126.8 (C-5), 127.4–139.3 (ArC), 142.1 (C-4), 170.8
A mixture of 1 mmol of pure spiroheterocycles (6Xa or 6Ya),
0.5 cm3 of concentrated hydrochloric acid, 10 cm3 of water and
6 cm3 of dioxane was heated at reflux for 1 hour, cooled, diluted
with water, and filtered to give the rearrangement product
which was purified by recrystallisation from methanol.
(C᎐O, acid), 182.7 (C᎐O, aroyl).
᎐
᎐
2-(4-Methylbenzoyl)-4-hydroxy-N-phenylpyrrole-5-acetic acid
10c. 10c (73 mg, 88%) as yellow solid mp: 153–155 ЊC (ethanol–
H2O); Found: C, 71.5; H, 5.0; N, 4.2; C20H17NO4 requires C,
71.6; H, 5.1; N, 4.1%; νmax(KBr)/cmϪ1: 3525–2850 ν (OH acid
1-ortho-Carboxyphenyl-3-phenylprop-2-enone 8a. 8a (250 mg,
100%) as beige solid mp: 155 ЊC (methanol); Found: C, 75.9; H,
4.7; C16H12O3 requires C, 76.2; H, 4.7%; νmax(KBr)/cmϪ1
:
and enol), 1720 (C᎐O, acid and aroyl); δ ([d6] DMSO) 2.40
᎐
H
3100–2530 ν (OH), 1690 (C᎐O, acid), 1645 (C᎐O); δH 7.00 (1H,
᎐
᎐
(3H, s, CH3), 3.40 (2H, s, CH2), 6.30 (1H, s, 3-H), 7.05–7.95
(9H, m, ArH ), 8.80 (1H, s, OH), 12.40 (1H, s, OH); δC ([d6]
DMSO) 21.0 (CH3), 29.0 (CH2), 109.9 (C-3), 121.7 (C-2), 126.9
d, J = 16.3 Hz, a-H), 7.20 (1H, d, J = 16.3 Hz, b-H), 7.35–8.10
(9H, m, ArH ), 10.45 (1H, s, OH); δC 120.2–141.5 (ArC and
C-1), 142.5 (C-4), 145.7 (C-5), 170.9 (C᎐O, acid), 196.7 (C᎐O).
᎐
᎐
(C-5), 127.6–141.6 (ArC), 142.0 (C-4), 170.8 (C᎐O, acid), 182.5
᎐
(C᎐O, aroyl).
᎐
Alkaline treatment of spiroadducts 6 and 7(a–d)
To a solution of spiroadducts (0.25 mmol) in 4.1 cm3 of ethanol
was added 0.9 cm3 of 2 M NaOH. The mixture was stirred at
room temperature for 2 hours, poured into an ice–water mix-
ture (100 cm3) and acidified with hydrochloric acid (or sulfuric
acid). After extraction with CH2Cl2 (20 cm3), the organic phase
was washed with water (2 × 20 cm3), dried (Na2SO4) and evap-
orated in vacuo. The crude products were purified by recrystal-
lisation from methanol 8a, 9b–e and without recrystallisation
(degradation) 10b–e.
2-(4-Methoxybenzoyl)-4-hydroxy-N-phenylpyrrole-5-acetic
acid 10d. 10d (52 mg, 60%) as brown solid mp: 131–132 ЊC
(ethanol–H2O); Found: C, 68.2; H, 4.9; N, 3.7; C20H17NO5
requires C, 68.3; H, 4.8; N, 4.0%; νmax(KBr)/cmϪ1: 3510–2840 ν
(OH acid and enol), 1720 (C᎐O, acid and aroyl); δ ([d6]
᎐
H
DMSO) 3.40 (2H, s, CH2), 3.90 (3H, s, CH3), 6.30 (1H, s, 3-H),
6.90–8.00 (9H, m, ArH ), 8.75 (1H, s, OH), 12.40 (1H, s, OH);
δC ([d6] DMSO) 29.0 (CH2), 55.4 (OCH3), 109.5 (C-3), 113.5–
162.1 (ArC), 121.1 (C-2), 127.1 (C-5), 141.9 (C-4), 170.9 (C᎐O,
᎐
The reaction leads to a quantitative yield for 8a and the yields
are given above for the other compounds.
acid), 181.7 (C᎐O, aroyl).
᎐
2-(4-Nitrobenzoyl)-4-hydroxy-N-phenylpyrrole-5-acetic acid
10e. 10e (60 mg, 66%) as orange solid mp: 199–201 ЊC (ethanol–
H2O); Found: C, 62.4; H, 3.9; N, 7.7; C19H14N2O6 requires C,
62.3; H, 3.8; N, 7.6%; νmax(KBr)/cmϪ1: 3545–2840 ν (OH acid
2-(4-Phenyl-1,4-dioxo-3-N-phenylaminobut-2-ene)benzoic
acid 9b. 9b (75 mg, 81%) as yellow solid mp: 145–147 ЊC (meth-
anol); Found: C, 74.5; H, 4.4; N, 3.7; C23H17NO4 requires C,
74.4; H, 4.6; N, 3.7%; νmax(KBr)/cmϪ1: 3190–2730 ν (OH and
and enol), 1700 (C᎐O, acid and aroyl); δ ([d6] DMSO) 3.40
᎐
H
NH), 1690 (C᎐O, acid), 1675 (C᎐O, aroyl); δ 5.70 (1H, s, ethyl-
᎐
᎐
H
(2H, s, CH2), 6.35 (1H, s, 3-H), 6.90–8.70 (9H, m, ArH ), 8.95
(1H, s, OH), 12.80 (1H, s, OH); δC ([d6] DMSO) 29.1 (CH2),
110.8 (C-3), 122.5–139.7 (ArC, C-2 and C-5), 142.5 (C-4), 170.6
enic), 6.80–8.20 (14H, m, ArH ), 8.65 (1H, s, OH), 12.20 (1H, s,
NH); δ 97.4 (HC᎐), 121.9–141.5 (ArC), 157.1 (C᎐), 171.4 (C᎐
᎐
᎐
᎐
C
O, acid), 191.5 (C᎐O, aroyl), 193.9 (C᎐O, aroyl).
᎐
᎐
(C᎐O, acid), 184.4 (C᎐O, aroyl).
᎐
᎐
2-[4-(4-Methylphenyl)-1,4-dioxo-3-N-phenylaminobut-2-ene]-
benzoic acid 9c. 9c (86 mg, 90%) as yellow solid mp: 161–163 ЊC
(methanol); Found: C, 74.6; H, 4.9; N, 3.7; C24H19NO4 requires
C, 74.8; H, 4.9; N, 3.6%; νmax(KBr)/cmϪ1: 3200–2740 ν (OH and
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NH), 1690 (C᎐O, acid), 1670 (C᎐O, aroyl); δ 2.45 (3H, s, CH ),
᎐
᎐
H
3
5.85 (1H, s, ethylenic), 6.95–8.35 (14H, m, ArH and OH), 12.40
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 6 8 9 – 2 6 9 8
2697

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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 6 8 9 – 2 6 9 8
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