Regio-and stereoselective 1,3-dipolar cycloaddition of C-aryl-N- phenylnitrones over (E)-arylidene-(2H)-indan-1-ones: Synthesis of highly substituted novel spiro-isoxazolidines

Article abstract of DOI:10.3987/COM-10-12022

Synthesis of a series of novel spiro-isoxazolidines has been accomplished in good yields by regio-and diastereoselective 1,3-dipolar cycloaddition of (E)-2-arylidene-(2H)-indan-1-ones 1a-d to C-aryl-N-phenylnitrones 2e-h. The structure of the spiro-adduct

Full text of DOI:10.3987/COM-10-12022

HETEROCYCLES, Vol. 81, No. 12, 2010
2749
HETEROCYCLES, Vol. 81, No. 12, 2010, pp. 2749 - 2762. © The Japan Institute of Heterocyclic Chemistry
Received, 17th July, 2010, Accepted, 21st October, 2010, Published online, 29th October, 2010
DOI: 10.3987/COM-10-12022
REGIO- AND STEREOSELECTIVE 1,3-DIPOLAR CYCLOADDITION OF
C-ARYL-N-PHENYLNITRONES OVER (E)-ARYLIDENE-(2H)-INDAN-
1-ONES: SYNTHESIS OF HIGHLY SUBSTITUTED NOVEL SPIRO-
ISOXAZOLIDINES
Nadia Wannassi,a Mohamed Mehdi Rammah,a Sarra Boudriga,a Mohamed El
Baker Rammah,a* Karin Monnier-Jobé,b* Kabula Ciamala,b Michael Knorr,b
Mironel Enescu,c Yoann Rousselin,d and Marek M. Kubickid
aLaboratory of Heterocyclic Organic Chemistry/LCOH, Department of Chemistry,
Faculty of Science of Monastir, 5000 Monastir, Tunisia
bInstitute UTINAM - UMR CNRS 6213, University of Franche-Comté, 16 Route
de Gray, F-25030 Besançon, France
cLaboratory of Physical Chemistry and Radiation Alain Chambaudet – UMR E4
CEA, 16 Route de Gray, F-25030 Besançon, France
dInstitute of Molecular Chemistry - UMR CNRS 5260 , University of Bourgogne, 9
Avenue A. Savary, F-21078 Dijon, France
Abstract – Synthesis of a series of novel spiro-isoxazolidines has been
accomplished in good yields by regio- and diastereoselective 1,3-dipolar
cycloaddition
of
(E)-2-arylidene-(2H)-indan-1-ones
1a-d
to
C-aryl-N-phenylnitrones 2e-h. The structure of the spiro-adducts 3ae-dh was
elucidated by 1H and 13C NMR spectroscopy. The proposed regio- and
stereochemistry of spiranic compounds 3ae and 3be has been corroborated by two
single crystal X-ray crystallographic analyses and by means of DFT calculations.
INTRODUCTION
The 1,3-dipolar cycloaddition reaction between nitrones and unsaturated systems is an efficient method
for the organic synthesis of a wide variety of new heterocyclic derivatives structurally related to lactams,
indolizidines, alkaloids1 which have found application in the preparation of complex molecules with
useful biological activities such as antibiotics and glycosidase inhibitors.2 For example Januário-Charmier
3–5
et al.
demonstrated that by conventional organic methods, chiral heterocycles of potential biological
activity, can be synthesized, exploring the fact that addition of nucleophiles to a C=C double bond offers

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HETEROCYCLES, Vol. 81, No. 12, 2010
an attractive route for the creation of novel C–C, N–O and C–O bonds and for the generation of new
isoxazolidine derivatives. These compounds have been for many products syntheses and can be converted
to efficient precursors for many synthetic intermediates including -amino alcohols,6 -amino acids7 and
-lactams,8 which are useful chiral building blocks for the synthesis of biologically active compounds.
Although numerous reports are available for the synthesis of isoxazolidine derivatives,9,10 relatively few
work on spiro-isoxazolidine derivatives has been published.
Further, many more indanone derivatives have been used as versatile intermediates for many natural and
pharmaceutical products.11-13 The high synthetic utility and pharmacological importance have prompted
us to synthesize some spiro-isoxazolidine derivatives which are potentially interesting in
pharmaceutical industry.
Since several years, we have focused our studies on the reactivity of dipolarophiles bearing an exocyclic
carbon-carbon double bond towards several 1,3-dipole such as nitrile oxides,14 diazoalkanes15 and
diarylnitrilimines.16 We particularly paid attention to the role played by the substituents of the dipolar
entities on both chemical reactivity and stereochemistry.
In continuation of our interest in the area of cycloaddition reactions, we present here the first examples
where C-aryl-N-phenylnitrones 2e-h reacted with (E)-2-arylidene-(2H)-indan-1-ones 1a-d in regio
selective manner. Previous to our investigation, to the best of our knowledge, there was only one report of
nitrone cycloaddition to trisubstituted olefins where the dipolarophiles had the reacting double bond
conjugated with an aryl group and a carbonyl group.17 Note that in the latter work, formation of
regioisomers has been observed.
RESULTS AND DISCUSSION
The synthetic route to the targeted spiro-isoxazolidines 3ae-dh is outlined in Scheme 1. Dipolarophiles
1a-d were obtained by the condensation of aromatic aldehydes with indanone.18,19
C-aryl-N-phenylnitrones 2e-h were easily generated by warming aryl aldehydes with
N-phenylhydroxylamine in ethanolic solution following a known procedure.20
The initial investigation on the 1,3-dipolar cycloaddition of (E)-2-arylidene-(2H)-indan-1-ones 1a-d with
C-aryl-N-phenylnitrones 2e-h involved the reaction of 1b with 2e at 110 °C in toluene solution for 24 h,
compound 3be was obtained in only 20% yield. Heating the same mixture at 80 °C for 24 h, afforded the
product 3be in 35% yield. Finally, the reaction of 1b with nitrone 2e in toluene at 80 °C for 6 days
yielded 3be (65%). Increase in reaction time from 6 days to 10 days did not allow improving the yield
further. On the basis of these results, we performed all cycloaddition reactions of dipolarophiles 1a-d
with C-aryl-N-phenylnitrones 2e-h at 80 °C in toluene for 6 days (Scheme 1). Yields of cycloadducts
3ae-dh range between 45-70% (Table 1).

HETEROCYCLES, Vol. 81, No. 12, 2010
2751
The reaction yielded exclusively in
a
regioselective manner,
a
series of the
spiro-[3,5-diaryl-2-isoxazolidine-4:2’-indan-1’-ones] 3ae-dh. The structure of each product was
established on the basis of spectroscopic and crystallographic analysis. In each case, the presence of
1
traces of starting reactants was also evidenced by TLC and H NMR examination of the crude reaction
mixture. These findings indicate that the reaction reaches an equilibrium state after 6 days. We suggest
that the selectivity should be, at least in part, thermodynamically controlled.
O-
Ph
Ar'
Ar
H
+
+
C
N
H
O
a : Ar = Ph
e : Ar' = Ph
1a-d
2e-h
toluene
80 °C
6 days
b : Ar = p-MeC6H4
c : Ar = p-MeOC6H4
d : Ar = p-ClC6H4
f : Ar' = p-MeC6H4
g : Ar' = p-MeOC6H4
h : Ar' = p-ClC6H4
H
Ar
H
Ar
H
1O
2N
Ar'
5
3
4
3
2N
4
5
2'
2'
1
O
1'
1'
Ph
Ph
H
Ar'
O
O
not observed
3ae-dh
3'ae-dh
Scheme 1. Reactions of C-aryl-N-phenylnitrones 2e-h with (E)-2-arylidene-(2H)-indan-1-ones 1ad
Table 1. Yields of spiro-isoxazolidines 3ae-dh
Entry
1
Dipolarophiles Nitrones Adductsa Yield(%)
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
1d
2e
2f
2g
2h
2e
2f
2g
2h
2e
2f
2g
2h
2e
2f
3ae
3af
45
64
60
50
65
60
70
52
50
50
49
55
60
45
50
50
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
3ag
3ah
3be
3bf
3bg
3bh
3ce
3cf
3cg
3ch
3de
3df
3dg
3dh
2g
2h
a Reaction in toluene at 80 °C during 6 days.

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HETEROCYCLES, Vol. 81, No. 12, 2010
The reaction is: (i) regioselective, since 3ae-dh with the oxygen of the nitrone added to the β-carbon of
the dipolarophile and (ii) stereoselective, as the two aryl of isoxazolidine ring of 3ae-dh are cis-arranged.
The regioselectivity is not unexpected since many examples have been reported of nitrone additions to
electron deficient alkenes to afford isoxazolidines with the oxygen in β-position to the
electron-withdrawing group.21-23
1
The H NMR spectra (300 MHz) exhibits a singlet between 5.40 ppm and 5.65 ppm assigned to the 3-H
proton. This excludes the presence of the inverse regioisomer, for which the NMR spectrum would
exhibit a doublet for 3-H. This was confirmed by the 13C NMR chemical shift of the spirocarbon (C-4,2’)
atoms of all adducts, which have been found between 68.69 ppm and 70.31 ppm. This range is in
agreement with the remoteness from the isoxazolidinic oxygen atom. 24,25 In the case of the hypothetic
isomeric structures 3’ae-dh, the chemical shift values of spiro carbon atoms (C-5,2’) should be around
82-84
ppm.26-29
The
cycloaddition
of
(E)-2-arylidene-(2H)-indan-1-ones
1a-d
with
C-aryl-N-phenylnitrones 2e-h led to cycloadducts 3ae-dh with three new chiral centers, i.e. the
quaternary spiroatom C-4,2’; C-3 and the C-5 of isoxazolidine ring (Scheme 1). The relative
stereochemistry of these carbon [rel-(3S, 4,2’R, 5R)] results from (i) preservation of the (E) configuration
of the initial olefin and (ii) concerted reaction of (Z)-nitrones 2e-h over 1a-d (Scheme 1). The formation
27-29
of diastereoisomeric adducts has never been caused by any Z/E interconversion of nitrones,
the
relative configuration (Z) of the dipole always being preserved in spiro-compounds (Figure 2, Scheme 1).
Furthermore, the suggested regio- and stereochemistry of 3ae-dh are supported by X-ray analyses carried
out on 3ae (Figure 2) and 3be (Figure 3). Before commenting these structures, one may consider different
approches during the course of the cycloaddition.
The two approach modes (endo-C=O and exo-C=O) of the C-aryl-N-phenylnitrones 2e-h towards
dipolarophiles 1a-d are depicted in Scheme 2.
O
O
O
N
N
O
Approach endo -C=O
favourable
Approach exo -C=O
unfavourable
Scheme 2. Endo-C=O and exo-C=O transition states for the reaction

HETEROCYCLES, Vol. 81, No. 12, 2010
2753
In order to clarify the origin of the selective formation of the endo –C=O product, we performed density
functional theory (DFT) optimisations of the complex of reactants in toluene at the B3LYP/6-31G(d)
level of theory. In these calculations the solvent was treated using the polarisable continuum dielectric
model of Cossi et al.30 The calculations were performed with the Gaussian 09 package. 31 We found that
the reactants form a site-to-site complex of endo –C=O type (Figure 1) that is very likely the precursor of
an endo –C=O transition state. It is well known that the site-to-site configuration is characteristic to
complexes mainly stabilized by electrostatic interactions. In the present case the complex appears to be
stabilized by hydrogen bonds involving the oxygen atoms carried by the two reactants. On the other hand,
an analogous conformation of the complex of the exo –C=O type was not identified in the calculations.
We conclude that the endo –C=O selectivity is due to a favourable electrostatic interaction between the
two reactants.
Figure 1. The calculations shows that the reactants form a site-to-site complex of endo –C=O type
Only
diastereoisomers
3ae
and
3be
resulting
from
the
cycloaddition
of
(E)-2-(benzylidene)-(2H)-indan-1-one 1a and (E)-2-(p-methylbenzylidene)-(2H)-indan-1-ones 1b with
C,N-diphenylnitrone 2b gave crystals of X-ray quality.
Because the space groups of the solid-state structures of both compounds contain the symmetry centres,
the diastereoisomers R(C10)S(C23) and S(C10)R(C23) (X-ray ORTEP label C10 corresponds to C3,
whereas C23 corresponds to C5 of Scheme 1) coexist in their racemic crystals. The H10 (3-H) and H23
(5-H) hydrogen atoms as well as the O2 one of carbonyl indanone ring point towards the same side of
isoxazolidine ring. A resulting endo (or cis) type geometry is more favourable since repulsion between
the O2 atom of indanone and the O1 and N1 atoms of central ring is thus avoided.

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HETEROCYCLES, Vol. 81, No. 12, 2010
Figure 2. ORTEP drawing of 3ae (50% probability level). One diastereoisomer (R(C10)S(C23); 3R5S) is
shown. Selected bond lengths (Å) and angles (°): N1-O1 1.462(2), C1-C10 1.546(2), C1-C23 1.545(3),
C1-C2 1.531(3), C1-C9 1.536(3), C10-N1 1.475(2), C23-O1 1.428(2); C2-C1-C9 105.94(15),
C10-C1-C23 97.83(14), C1-C10-N1 102.96(14), C1-C23-O1 103.26(15)
Figure 3. ORTEP drawing of 3be (50% probability level). One diastereoisomer (S(C10)R(C23); 3S5R) is
shown. Selected bond lengths (Å) and angles (°): N1-O1 1.4488(15), C1-C10 1.552(2), C1-C23 1.544(2),
C1-C2 1.537(2), C1-C9 1.537(2), C10-N1 1.492(2), C23-O1 1.4368(17), C2-C1-C9 105.32(12),
C10-C1-C23 98.74(11), C1-C10-N1 104.16(11), C1-C23-O1 102.37(11)
Because of the presence of three adjacent sp3 carbon atoms (C10, C1 and C23), the isoxazolidine rings
deviate strongly from planarity. The C10/N1/O1/C23 fragment is planar within 0.05 and 0.10 Å in 3ae
and 3be, respectively. The dihedral angles with the C10/C1/C23 plane are equal to 42.4(9) and 40.1(1)° in
3ae and 3be, respectively. Contrary to the isoxazolidine ring, the five-membered indanone ring (one sp3
carbon) fits very well the best least-square plane with highest deviations from reaching only 0.01 and
0.009 Å, respectively. The spiranic dihedral angles of 89.5(1) 3ae and 87.8(1)° 3be are close to the ideal

HETEROCYCLES, Vol. 81, No. 12, 2010
2755
value of 90° for regular tetrahedral Td spirane. The metric parameters are normal in both structures.
CONCLUSION
In conclusion, we have shown that cycloaddition reaction of (E)-2-arylidene-(2H)-indan-1-ones 1a-d with
nitrones 2e-h leads regio- and diastereoselectively (100%) to
spiro-[3,5-diaryl-2-isoxazolidine-4:2’-indan-1’-ones]. The regiochemistry of the reaction is independent
to the electronic nature of the substituents at the para-position on the dipolarophile as well as on the
dipole. The exclusive stereoselectivity of the reaction has been rationalised to be a consequence of
combined electronic and steric interactions of the reagents during their approaches. The diastereoisomers
3ae-dh are the result of the preferential approach directing the indanone carbonyl group in the endo
position relative to the dipolar linkage. Apart from the regioselectivity aspect, the novel
spiro-isoxazolidines presented in this work should be of interest as precursors for the synthesis of a
variety of amino-alcohols derivatives.
EXPERIMENTAL
General Remarks: Reactions were carried out under an atmosphere of dry N2. Solvents were purified by
standard methods and freshly distilled under nitrogen and dried before use.
Melting points were determined on a Kofler bank. IR spectra were recorded from KBr on a Perkin-Elmer
197 spectrometer; only structurally significant bands are reported. NMR spectra were recorded with a
1
Bruker-Spectrospin AC 300 spectrometer operating at 300 MHz for H and 75.5 MHz for 13C using
tetramethylsilane (TMS) as the internal standard (0.00 ppm) in CDCl3 as solvent. Chemical shifts were
reported in ppm () downfield from TMS. The following abbreviations were used to explain the
multiplicities: s =singlet, d = doublet, t = triplet, m = multiplet.
Elemental analyses (C, H, N) were conducted on a Leco Elemental CHN 900; values were in satisfactory
agreement with the calculated ones (0.30%). Materials: thin-layer chromatography (TLC): TLC plates
(Merck, silica gel 60 F254 0.2 mm 200200 nm); substances were detected using UV light at 254 nm.
(E)-2-Arylidene-(2H)-indan-1-ones 1a-d were obtained by condensation of aldehydes ArCHO with
respectively indanone according to reported methods.28,29,32 C-Aryl-N-phenylnitrones 2e-h was
synthesized as reported by condensation of aldehydes Ar’CHO with phenylhydroxylamine.33
General procedure for the preparation of the cycloadducts (3ae-dh)
A solution of dipolarophiles 1a-d (3 mmol) and C-aryl-N-phenylnitrones (3 mmol) 2e-h in dry toluene
(10 mL), was stirred at 80 °C for 6 days. The solvent was evaporated under reduced pressure and the

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HETEROCYCLES, Vol. 81, No. 12, 2010
residue was purified by column chromatography on silica gel eluted with hexane/EtOAc (20:80) to afford
compounds 3ae-dh.
Spiro[3,5-diphenyl -2-isoxazolidine-4:2’-indan-1’-ones] (3ae)
Yield 0.56 g (45%); white solid; mp 122 °C; IR (KBr, cm-1): 1751, 1615; 1H NMR (CDCl3):  2.75 (d, J=
18 Hz, 3’-H); 2.85 (d, J= 18 Hz, 3’-H); 5.45 (s, 3-H); 5.60 (s, 5-H); 6.78-8.30 (m, aromatic H); 13C NMR
(CDCl3):  30.57 (C-3’); 70.31 (C-4.2’); 79.20 (C-3); 86.64 (C-5); 114.95-154.24 (aromatic C); 204.36
(C-1’); Anal. Calcd for C29H23NO2: C, 83.43; H, 5.55; N, 3.35. Found: C, 83.25; H, 5.40; N, 3.21.
Spiro[3-phenyl-5-(p-tolyl)-2-isoxazolidine-4:2’-indan-1’-one] (3af)
1
Yield 0.82 g (64%); yellow solid; mp 126 °C; IR (KBr, cm-1): 1740, 1613; H NMR (CDCl3):  2.20 (s,
CH3); 2.75 (d, J= 18 Hz, 3’-H); 2.85 (d, J= 18 Hz, 3’-H); 3’-H); 5.40 (s, 3-H); 5.60 (s, 5-H); 6.85-7.75 (m,
13
aromatic H); C NMR (CDCl3):  21.44 (CH3); 30.53 (C-3’); 70.25 (C-4,2’); 79.02 (C-3); 86.62 (C-5);
114.96-154.32 (aromatic C); 204.40 (C-1’). Anal. Calcd for C30H25NO2: C, 83.50; H, 5.84; N, 3.25.
Found: C, 83.29; H, 5.96; N, 3.34.
Spiro[5-(p-anisyl)-3-phenyl-2-isoxazolidine-4:2’-indan-1’-one] (3ag)
1
Yield 0.80 g (60%); yellow solid; mp 165 °C; IR (KBr, cm-1): 1742, 1612; H NMR (CDCl3):  2.83 (d,
J= 18 Hz, 3’-H); 2.93 (d, J= 18 Hz, 3’-H); 3.75 (s, OCH3); 5.47 (s, 3-H); 5.50 (s, 5-H); 6.75 -7.70 (m,
aromatic H);13C NMR (CDCl3):  30.19 (C-3’); 55.30 (s, OCH3); 69.90 (C-4,2’); 78.45 (C-3); 86.57
(C-5); 113.40-159.20 (aromatic C); 204.28 (C-1’). Anal. Calcd for C30H25NO3: C, 80.51; H, 5.63; N, 3.13.
Found: C, 80.25; H, 5.35; N, 2.97.
Spiro[5-(p-chlorophenyl)-3-phenyl-2-isoxazolidine-4:2’-indan-1’-one] (3ah)
Yield 0.67g (50%); white solid; mp 149 °C; IR (KBr, cm-1): 1753, 1613; 1H NMR (CDCl3):  2.90 (d, J=
18 Hz, 3’-H); 3.00 (d, J= 18 Hz, 3’-H); 5.63 (s, 3-H); 5.72 (s, 5-H); 7.03-7.85 (m, aromatic H); 13C NMR
(CDCl3):  29.06 (C-3’); 68.69 (C-4,2’); 77.72 (C-3); 83.95 (C-5); 113.60-152.64 (aromatic C); 202.67
(C-1’). Anal. Calcd for C29H22NO2Cl: C, 77.07; H, 4.91; N, 3.10. Found: C, 76.89; H, 4.72; N, 3.33.
Spiro[5-phenyl-3-(p-tolyl)- 2-isoxazolidine-4:2’-indan-1’-one] (3be)
1
Yield 0.84g (65%); yellow solid; mp 126 °C; IR (KBr, cm-1): 1755, 1613; H NMR (CDCl3):  2.27 (s,
CH3); 2.84 (d, J= 18 Hz, 3’-H); 2.94 (d, J= 18 Hz, 3’-H); 5.54 (s, 3-H); 5.63 (s, 5-H); 6.91-7.76 (m,
13
aromatic H); C NMR (CDCl3):  21.19 (CH3); 30.16 (C-3’); 69.86 (C-4,2’); 78.69 (C-3); 86.31 (C-5);

HETEROCYCLES, Vol. 81, No. 12, 2010
2757
114.57-154.01 (aromatic C); 204.14 (C-1’). Anal. Calcd for C30H25NO2: C, 83.50; H, 5.84; N, 3.25.
Found: C, 83.33; H, 5.58; N, 3.06.
Spiro[3,5-di(p-tolyl)-2-isoxazolidine-4:2’-indan-1’-one] (3bf)
1
Yield 0.80 g (60%); yellow solid; mp 195 °C; IR (KBr, cm-1): 1757, 1614; H NMR (CDCl3):  2.40 (s,
CH3); 2.42 (s, CH3); 2.80 (d, J= 18 Hz, 3’-H); 2.90 (d, J= 18 Hz, 3’-H); 5.45 (s, 3-H); 5.59 (s, 5-H);
6.87-7.77 (m, aromatic H); 13C NMR (CDCl3):  21.30 (s, CH3); 21.35 (s, CH3); 30.33 (C-3’); 70.14
(C-4,2’); 78.74 (C-3); 86.42 (C-5); 114.62-154.24 (aromatic C); 204.26 (C-1’). Anal. Calcd for
C31H27NO2: C, 83.57; H, 6.11; N, 3.14. Found: C, 83.75; H, 6.25; N, 2.97.
Spiro[5-(p-anisyl)-3-(p-tolyl)-2-isoxazolidine-4:2’-indan-1’-one] (3bg)
1
Yield 0.96 g (70%); yellow solid; mp 190 °C; IR (KBr, cm-1): 1754, 1614; H NMR (CDCl3):  2.40 (s,
CH3); 2.96 (d, J= 18 Hz, 3’-H); 3.06 (d, J= 18 Hz, 3’-H); 3.80 (s, OCH3); 5.46 (s, 3-H); 5.63 (s, 5-H);
13
6.70-7.75 (m, aromatic H); C NMR (CDCl3):  21.51 (s, CH3); 30.35 (C-3’); 55.61 (s, OCH3); 70.10
(C-4,2’); 78.35 (C-3); 85.98 (C-5); 113.62-158.54 (aromatic C); 204.26 (C-1’). Anal. Calcd for
C31H27NO3: C, 80.67; H, 5.90; N, 3.03. Found: C, 80.82; H, 5.62; N, 2.91.
Spiro[5-(p-chlorophenyl)-3-(p-tolyl)- 2-isoxazolidine-4:2’-indan-1’-one] (3bh)
1
Yield 0.72 g (52%); white solid; mp 175 °C; IR (KBr, cm-1): 1735, 1612; H NMR (CDCl3):  2.45 (s,
CH3); 3.07 (d, J= 18 Hz, 3’-H); 3.17 (d, J= 18 Hz, 3’-H); 5.61 (s, 3-H); 5.73 (s, 5-H); 7.26-7.85 (m,
13
aromatic H); C NMR (CDCl3):  22.40 (CH3); 30.40 (C-3’); 68.77 (C-4,2’); 77.73 (C-3); 85.45 (C-5);
115.64-153.30 (aromatic C); 204.20 (C-1’). Anal. Calcd for C30H24NO2Cl: C, 77.33; H, 5.19; N, 3.01.
Found: C, 77.13; H, 5.04; N, 3.20.
Spiro[3-(p-anisyl)-5-phenyl-2-isoxazolidine-4:2’-indan-1’-one] (3ce)
1
Yield 0.67 g (50%); yellow solid; mp 186 °C; IR (KBr, cm-1): 1732, 1615; H NMR (CDCl3):  2.84 (d,
J= 18 Hz, 3’-H); 2.94 (d, J= 18 Hz, 3’-H); 3.77 (s, OCH3); 5.48 (s, 3-H); 5.52 (s, 5-H); 6.73 -7.85 (m,
aromatic H); 13C NMR (CDCl3):  30.25 (C-3’); 55.31 (s, OCH3); 69.95 (C-4,2’); 78.46 (C-3); 86.60
(C-5); 113.45-159.25 (aromatic C); 204.30 (C-1’). Anal. Calcd for C30H25NO3: C, 80.51; H, 5.63; N,
3.13. Found: C, 80.34; H, 5.37; N, 2.94.
Spiro[3-(p-anisyl)-5-(p-tolyl)-2-isoxazolidine-4:2’-indan-1’-one] (3cf)
1
Yield 0.69 g (50%); yellow solid; mp 180 °C; IR (KBr, cm-1): 1754, 1612; H NMR (CDCl3):  2.39 (s,

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CH3); 2.92 (d, J= 18 Hz, 3’-H); 3.02 (d, J= 18 Hz, 3’-H); 3.85 (s, OCH3); 5.48 (s, 3-H); 5.60 (s, 5-H);
13
6.70-7.75 (m, aromatic H); C NMR (CDCl3):  21.50 (s, CH3); 30.89 (C-3’); 55.65 (s, OCH3); 70.12
(C-4,2’); 78.40 (C-3); 85.97 (C-5); 113.62-158.55 (aromatic C); 204.27 (C-1’). Anal. Calcd for
C31H27NO3: C, 80.67; H, 5.90; N, 3.03. Found: C, 80.79; H, 6.03; N, 2.88.
Spiro[3,5-di(p-anisyl)-2-isoxazolidine-4:2’-indan-1’-one] (3cg)
1
Yield 0.70 g (49%); yellow solid; mp 138 °C; IR (KBr, cm-1): 1752, 1613; H NMR (CDCl3):  2.84 (d,
J= 18 Hz, 3’-H); 2.94 (d, J= 18 Hz, 3’-H); 3.70 (s, OCH3); 3.74 (s, OCH3); 5.47 (s, 3-H); 5.59 (s, 5-H);
6.68-7.73 (m, aromatic H); 13C NMR (CDCl3):  30.04 (C-3’); 55.23 (OCH3); 55.28 (OCH3); 69.97
(C-4,2’); 78.52 (C-3); 86.14 (C-5); 113.54-159.31 (aromatic C); 204.29 (C-1’). Anal. Calcd for
C31H27NO4: C, 77.97; H, 5.70; N, 2.93. Found: C, 78.14; H, 5.44; N, 2.67.
Spiro[3-(p-anisyl)-5-(p-chlorophenyl)-2-isoxazolidine-4:2’-indan-1’-one] (3ch)
Yield 0.79 g (55%); white solid; mp 196 °C; IR (KBr, cm-1): 1753, 1613; 1H NMR (CDCl3):  2.85 (d, J=
18 Hz, 3’-H); 2.95 (d, J= 18 Hz, 3’-H); 3.84 (s, OCH3); 5.49 (s, 3-H); 5.61 (s, 5-H); 6.72-7.75 (m,
aromatic H); 13C NMR (CDCl3):  30.42 (C-3’); 55.25 (OCH3); 70.12 (C-4,2’); 78.55 (C-3); 85.30 (C-5);
113.62-160.40 (aromatic C); 204.25 (C-1’). Anal. Calcd for C30H24NO3Cl: C, 74.76; H, 5.02; N, 2.91.
Found: C, 74.63; H, 5.23; N, 2.67.
Spiro[3-(p-chlorophenyl)-5-phenyl-2-isoxazolidine-4:2’-indan-1’-one] (3de)
1
Yield 0.81 g (60%); yellow solid; mp 176 °C; IR (KBr, cm-1): 1755, 1614; H NMR (CDCl3):  2.84 (d,
13
J= 18 Hz, 3’-H); 2.94 (d, J= 18 Hz, 3’-H); 5.65 (s, 3-H); 5.69 (s, 5-H); 6.99-7.80 (m, aromatic H); C
NMR (CDCl3):  29.26 (C-3’); 68.73 (C-4,2’); 77.68 (C-3); 83.98 (C-5); 114.30-155.25 (aromatic C);
203.99 (C-1’). Anal. Calcd for C29H22NO2Cl: C, 77.07; H, 4.91; N, 3.10. Found: C, 76.90; H, 4.73; N,
3.30.
Spiro[3-(p-chlorophenyl)-5-(p-tolyl)-2-isoxazolidine-4:2’-indan-1’-one] (3df)
Yield 0.62 g (45%); yellow solid; mp 230 °C; IR (KBr, cm-1): 1753, 1614 cm-1; 1H NMR (CDCl3):  2.40
(s, CH3); 3.09 (d, J= 18 Hz, 3’-H); 3.19 (d, J= 18 Hz, 3’-H); 5.63 (s, 3-H); 5.70 (s, 5-H); 7.26-7.85 (m,
13
aromatic H); C NMR (CDCl3):  22.39 (CH3); 30.36 (C-3’); 68.75 (C-4,2’); 77.70 (C-3); 85.41 (C-5);
115.63-155.27 (aromatic C); 202.71 (C-1’). Anal. Calcd for C30H24NO2Cl: C, 77.33; H, 5.19; N, 3.01.
Found: C, 77.10; H, 5.06; N, 3.19.

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Spiro[5-(p-anisyl)-3-(p-chlorophenyl)-2-isoxazolidine-4:2’-indan-1’-one] (3dg)
Yield 0.72 g (50%); yellow solid; mp 188 °C; IR (KBr, cm-1): 1752, 1615 cm-1; 1H NMR (CDCl3):  2.87
(d, J= 18 Hz, 3’-H); 2.97 (d, J= 18 Hz, 3’-H); 3.82 (s, OCH3); 5.50 (s, 3-H); 5.62 (s, 5-H); 7.71-7.77 (m,
aromatic H); 13C NMR (CDCl3):  30.140 (C-3’); 55.26 (OCH3); 70.10 (C-4,2’); 78.48 (C-3); 85.37
(C-5); 113.60-160.43 (aromatic C); 203.98 (C-1’). Anal. Calcd for C30H24NO3Cl: C, 74.76; H, 5.02; N,
2.91. Found: C, 74.62; H, 5.25; N, 2.68.
Spiro[3,5-di(p-chlorophenyl)-2-isoxazolidine-4:2’-indan-1’-one] (3dh)
Yield 0.72 g (50%); white solid; mp 170 °C; IR (KBr, cm-1): 1751, 1615; 1H NMR (CDCl3):  2.90 (d, J=
18 Hz, 3’-H); 3.00 (d, J= 18 Hz, 3’-H); 5.62 (s, 3-H); 5.71 (s, 5-H); 7.69-7.79 (m, aromatic H); 13C NMR
(CDCl3):  30.15 (C-3’); 70.16 (C-4,2’); 78.52 (C-3); 85.91 (C-5); 113.58-160.40 (aromatic C); 204.18
(C-1’). Anal. Calcd for C29H21NO2Cl2: C, 71.61; H, 4.35; N, 2.88. Found: C, 71.43; H, 4.44; N, 2.76.
X-Ray structure analyses
X-Ray quality colorless crystals of 3ae (0.42x0.20x0.20 mm) and 3be (0.30x0.25x0.07 mm), grown from
ethanol solutions, were mounted on a Nonius KappaCCD diffractometer. Intensity data were collected
at 115 K with Mo-K radiation. The crystal structures were solved by direct methods34 and refined with
full-matrix least squares on F2.35 Anisotropic thermal parameters were applied for non-hydrogen atoms.
All H atoms were placed in calculated positions and included in final refinements in a riding model with
isotropic temperature factors related to the carbon atoms bearing them: Uiso(H) = 1.2Ueq(C). There is a
slight disorder in both structures. It concernes the four aromatic CH groups of indanone ring in 3ae
(refined occupancies are 0.55/0.45), whereas in 3be the disorder is observed for phenyl group bound to
C10 atom of the central ring with occupancies 0.61/0.39. These disorders are certainly due to the crystal
packing.
X-Ray crystal structure analyses of compounds (3ae) and (3be):
For C29H23NO2 : M = 417.48, monoclinic, space group P21/c, a = 10.2526(1) Å, b = 19.8492(3) Å, c =
11.1911(2) Å, β = 104.151(1)°, V = 2208.34(6) Å3, Z = 4, Dc = 1.256 Mg/m3, (Mo-Kα) = 0.71073 Å,
F(000) = 880, (Mo-K) = 0.078 mm-3, T = 115(2) K. 9878 reflections collected, 5022 unique and 3881
with I>2(I). Final residuals max = 0.247, min = -0.192 e-/Å3. Final agreement factors: R(F) = 0.0555
and 0.0757, wR(F2) = 0.1259 and 0.1325 for I>2(I) and all data, respectively, GOF = 1.143.
For C30H25NO2 : M = 431.51 triclinic, space group P-1, a = 8.3336(2) Å, b = 9.5701(3) Å, c = 15.3515(4)
Å, α = 81.393(2)°, β = 79.535(2)°, γ = 68.349(1)°, V = 1114.44(5) Å3, Z = 2, Dc = 1.286 Mg/m3,
(MoKα) = 0.71073 Å, F(000) = 456, (Mo-K) = 0.080 mm-3, T = 115(2) K. 9798 reflections collected,

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5101 unique and 3448 with I>2(I). Final residuals max = 0.328, min = -0.298 e-/Å3. Final agreement
factors: R(F) = 0.0496 and 0.0845, wR(F2) = 0.1195 and 0.1360 for I>2(I) and all data, respectively,
GOF = 1.050.
Crystallographic data for the structures of 3ae and 3be have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number 782615 and 782616. Copy of these
data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 IEZ, UK,
fax: 144-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk.
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