Regioselective synthesis and structure of new spiro-isoquinolinedione derivatives

Article abstract of DOI:10.3987/COM-09-11874

New spiro-isoquinolinoisoxazolines were prepared by regioselective 1,3-dipolar cycloaddition of 4-arylidene-isoquinoline-1,3-dione derivatives 1a-d with arylnitrile oxides 2e-g. In all cases, two regioisomers 3ae-dg and 4ae-dg were isolated with comparabl

Full text of DOI:10.3987/COM-09-11874

HETEROCYCLES, Vol. 81, No. 3, 2010
707
HETEROCYCLES, Vol. 81, No. 3, 2010, pp. 707 - 715. © The Japan Institute of Heterocyclic Chemistry
Received, 20th November, 2009, Accepted, 24th December, 2009, Published online, 28th December, 2009
DOI: 10.3987/COM-09-11874
REGIOSELECTIVE SYNTHESIS AND STRUCTURE OF NEW
SPIRO-ISOQUINOLINEDIONE DERIVATIVES
Nafâa Jegham, Yakdhane Kacem, and Béchir Ben Hassine*
Laboratoire de Synthèse Organique Asymétrique et Catalyse Homogène (01 UR
1201), Faculté des Sciences de Monastir, Avenue de l’Environnement, 5019,
Monastir, Tunisie
Abstract – New spiro-isoquinolinoisoxazolines were prepared by regioselective
1,3-dipolar cycloaddition of 4-arylidene-isoquinoline-1,3-dione derivatives 1a-d
with arylnitrile oxides 2e-g. In all cases, two regioisomers 3ae-dg and 4ae-dg
were isolated with comparable ratios. Regioselectivity was established by
unambiguous structural NMR assignments and X-ray diffraction analysis.
4-Spiroisoquinoline derivatives have gained an increasing interest in recent years thanks to their potential
bioactivity1,2 and their versatile utility as precursors in the preparation of numerous biologically-active
products.3 These compounds have been synthesised using various methods4 essentially by 1,3-dipolar
cycloaddition reactions to the exocyclic C-C double bond of specific isoquinoline-4-ylidene derivatives.
This method has proven to be an excellent synthetic route however, few examples of the synthesis of such
systems by means of cycloaddition are reported in the literature.5 4-Spiroisoquinoline can also be
prepared by an intramolecular cyclisation with suitable chain at position 4 of isoquinoline derivatives.6
As an extension of our work in the field towards the synthesis of spiroisoquinolines,7 we report herein an
efficient and practical procedure for the preparation of new spiro-isoquinolinoisoxazolines 3ae-dg and
4ae-dg by 1,3-dipolar cycloaddition of ylidene isoquinoline-1,3-dione derivatives with arylnitrile oxides.
This approach also allows access to spiroheterocycles having very important biological activities.8
The synthetic route to the targeted spiro-isoquinolinoisoxazolines 3ae-dg and 4ae-dg is outlined in
Scheme 1. Dipolarophiles 1a-d were obtained by the condensation of aromatic aldehydes with
N-phenyl-(2H)-homophthalimide. Arylnitrile oxides 2e-g were easily generated in situ from
benzohydroxyaminoyl chlorides with triethylamine in toluene following a known procedure.9
Cycloaddition reaction of dipolarophiles 1a-d with the arylnitrile oxides 2e-g at reflux of toluene within

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48 h afforded the two regioisomers spiro-isoquinolinoisoxazolines 3ae-dg and 4ae-dg with good
chemical yields and comparable ratios as shown in Table1.
R'
R
R'
2
N
1
O
3
C
N2
O1
H
H
N
R
R
H
C3
NEt3/Toluene
reflux 48h
4
5
4
5
+
C
N OH
O
R'
O
O
+
4'
4'
3'
3'
Cl
N
N
Ph
2'
Ph
2' Ph
1'
1'
O
O
O
(E)-1a-d
a : R = H
2e-g
e : R = H
3ae-dg
4ae-dg
b : R = Me
c : R = OMe
d : R = NO2
f : R = Me
g : R = OMe
Scheme 1. [3+2] Cycloaddition reaction of benzohydroxyaminoyl chlorides 2e-g
with (E)-4-arylidene-isoquinoline-1,3-diones 1a-d
Table 1. Selected data for compounds 3ae-dg and 4ae-dg
Ratios
3/4
1H NMR
(δH4 and δH5 ) (δC5,4’ and δC4,4’)
13C NMR
Cycloadducts
3/4
Entry
R
R’
1
2
H
Me
OMe
NO2
H
H
H
3ae/4ae
68/32
65/35
71//29
73/27
67/33
66/34
70/30
71/29
72/28
70/30
69/31
68/32
5.24/6.26
5.23/6.25
5.21/6.23
5.25/6.28
5.22/6.19
5.21/6.16
5.20/6.12
5.24/6.22
5.21/6.29
5.20/6.25
5.18/6.21
5.20/6.27
90.74/70.82
90.80/70.77
90.39/70.83
90.90 /70.87
90.61/70.90
90.67/70.86
90.58/70.85
90.76/70.94
90.57/70.94
90.57/70.92
90.53/70.92
90.60/70.97
3be/4be
3ce/4ce
3de/4de
3af/4af
3bf/4bf
3cf/3’cf
3df/4df
3ag/4ag
3bg/4bg
3cg/4cg
3dg/4dg
3
H
4
5
H
Me
Me
Me
Me
OMe
OMe
6
7
Me
OMe
NO2
H
8
9
10
11
12
Me
OMe OMe
NO2 OMe
During this study, we have submitted dipolarophiles 1a-d to cycloaddition reaction with the arylnitrile
1
oxides 2e-g leading to a mixture of two adducts as evidenced by TLC and H NMR examination of the
crude mixture. The pairs of cycloadducts 3ae-dg and 4ae-dg are usually formed in fair yields and have
been separated by column chromatography. The structures of two cycloadducts were established on the
basis of spectroscopic and crystallographic data. According to X-ray crystal analysis the two cycloadducts
are regioisomers as result of two different ways of approach of benzohydroxyaminoyl chlorides (2e-g) to

HETEROCYCLES, Vol. 81, No. 3, 2010
709
the C=C exocyclic double bond of (E)-4-arylidene-N-phenyl-(2H)-isoquinoline-1,3-dione (1a-d). In each
case, the mixture of two regioisomers is obtained in comparable ratios ranging closely around 70/30.
These ratios were determined by the integration of the benzylic protons H-4 and H-5 signals in the NMR
spectra of the crude mixture and closely correspond to those obtained in the separation. In order to have
more regioselectivity, the cycloadditions have been performed in different solvents: toluene, benzene and
chloroform at reflux and at room temperature. Unfortunately, we have found that variation of reaction
conditions showed very little modifications in the ratios of formed regioisomers.
The regiochemistry of the reaction was not similar to that observed in the case of an olefin activated by an
electron-withdrawing group, which was always situated at the position 5 of the resulting spiroisoxazoline
1
derivatives.7,10 The H NMR spectra of regioisomers 3ae-dg exhibited a signal around δ= 5.18-5.25 ppm
13
attributed to the proton H-4. The C NMR data also confirmed this result. The chemical shifts of the
spiro carbon atoms (C-5, 4’) were found to be between 90.39-90.90 ppm because of the deshielding effect
1
of the oxygen atom. In the case of structures 4ae-dg, the H NMR spectra are similar to that of
regioisomers 3ae-dg but show more deshielded signals for H-5 (δ=6.12-6.29 ppm) while chemical shift
values of the spiro carbon atoms (C-4,4’) were between 70.77-70.97 ppm. The suggested regiochemistry
of 3ae-dg and 4ae-dg was furthermore supported by X-ray analysis (Figures 1 and 2). The cycloadducts
3ae-dg and 4ae-dg present respectively two new chiral centers, i.e the quaternary spiroatom and C-4 or
C-5 of isoxazole ring. The relative stereochemistry of these carbon results from preservation of the (E)
configuration of the initial olefin. The stereochemistry of the cycloadducts was corroborated by an X-ray
crystal analysis of the spiroadducts 3cg and 4ag.
Figure 1. ORTEP of compound 3cg
Figure 2. ORTEP of compound 4ag
We have shown an efficient and simple route to 4-spiroisoquinoline derivatives by 1,3-dipolar
cycloaddition which continue to attract the attention of both synthetic chemists and pharmacologists. The

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cycloaddition reaction of arylnitrile oxides with (E)-4-arylideneisoquinoline-1,3-dione derivatives leads
to two regioisomers and the regiochemistry of the reaction was explained using spectroscopic and
crystallographic data.
EXPERIMENTAL
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. N-Phenyl homophthalimide were prepared
according to the reported method.11 Melting points were determined on a Kofler bank and were
uncorrected. NMR spectra were recorded on a Bruker-spectrospin AC 300 spectrometer, operating at 300
MHz for 1H and 75.5 MHz for 13C. Chemical shifts were measured relative to TMS in CDCl3 as solvent.
Elemental analyses were carried out by the service of Microanalyse of the ‘‘Institut National de
Recherche et d’Analyse Physico-Chimique de Tunis’’.
The crystal data for C31H24N2O5 (3cg) and C30H22N2O4 (4ag) were recorded on a Bruker-APEX II CCD
diffractometer. 3cg: M = 504.52, Monoclinic, P21/c, a = 12.2441 (6) Å, b = 9.73941 (4) Å, c =23.0227
(11) Å, V = 2610.1 (2) Å3, Z = 4, Dc = 1.284 Mg/m3, X-ray source Mo K (radiation), k = 0.71070 Å, F
(000) = 1056, T = 296(2) K, white prism 0.44 × 0.30 × 0.23 mm. The structure was worked out by direct
methods and refined anisotropically using a full-matrix with least squares based on F2 to give R1 =
0.0498, wR2 = 0.1018 for 5398 independent observed reflections and 416 parameters. Crystallographic
data (excluding structure factors) for the structure in this paper have been deposited with the Cambridge
Crystallographic Data Center as a supplementary publication number CCDC 738431. 4ag: M= 474.50,
Monoclinic, P21/c, a = 9.8754 (3) Å, b =22.7765 (8) Å, c =10.7281 (4) Å, V =2359.85 (14) Å3, Z =4, Dc =
1.336 Mg/m3, X-ray source Mo K (radiation), k = 0.71070 Å, F (000) = 992, T = 293(2) K, white prism
0.30 × 0.20 × 0.18 mm. The structure was worked out by direct methods and refined anisotropically using
a full-matrix with least squares based on F2 to give R1 = 0.0550, wR2 = 0.1588 for 5602 independent
observed reflections and 326 parameters. Crystallographic data (excluding structure factors) for the
structure in this paper have been deposited with the Cambridge Crystallographic Data Center as a
supplementary publication number CCDC 735594. Copies of the Crystallographic data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
+44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
General procedure for the preparation of the dipolarophiles
(E)-4-Arylidene-N-phenyl-(2H)-isoquinoline-1,3-dione were obtained by the condensation of aromatic
aldehydes with N-phenyl-(2H)-homophthalimide in dry chloroform in the presence of piperidine. The
residue was recrystallised from EtOH to give products (1a-d).

HETEROCYCLES, Vol. 81, No. 3, 2010
711
General procedure for the preparation of the spirocycloadducts
A magnetically stirred solution of (E)-4-arylidene-N-phenyl-(2H)-isoquinoline-1,3-dione (1a-d) and the
appropriate precursor of benzohydroxyaminoyl chlorides (2e-g) in dry toluene, was refluxed under
nitrogen for 15 min. Et3N (2 mL) was then added and the mixture was stirred and refluxed for 48 h. After
the filtration of triethylamine hydrochloride, the solvent was evaporated and the residue was purified by
chromatography on silica gel (eluent: cyclohexane-AcOEt, 90:10).
(4S*,5:4’R*)-Spiro[3,4-diphenylisoxazoline-5,4’-(2’-phenyl)isoquinoline-1’,3’-dione] (3ae): Yield
(60%); white solid; Mp 196 °C; 1H NMR (300 MHz, CDCl3): δ 5.24 (s, 4-H), 6.67-7.79 (m, aromatic H)
ppm; 13C NMR: (75.5 MHz, CDCl3) δ 67.00 (C-4), 90.74 (C-5.4’), 125.17-159.09 (C-3 and aromatic C),
168.40 (C=O); 171.92 (C=O) ppm. Anal. Calcd for C29H20N2O3: C, 78.36; H, 4.54; N, 6.30. Found: C,
78.44; H, 4.62; N, 6.40.
(5R*,4:4’R*)-Spiro[3,5-diphenylisoxazoline-4,4’-(2’–phenyl)isoquinoline-1’,3’-dione] (4ae): Yield
(22%); yellow solid; Mp 176 °C; 1H NMR (300 MHz, CDCl3): δ 6.26 (s,5-H) , 6.75-8.03 (m, aromatic H)
13
ppm; C NMR (75.5 MHz, CDCl3) δ 97.52 (C-5), 70.82 (C-4,4’), 124.94-159.84 (C-3 and aromatic C),
168.35 (C=O), 171.22 (C=O) ppm.
(4S*,5:4’R*)-Spiro[3-phenyl-4-(p-tolyl)isoxazoline-5,4’-(2’-phenyl)isoquinoline-1’,3’-dione] (3be):
1
Yield (59%); white solid; Mp 230 °C; H NMR (300 MHz, CDCl3) δ 2.20 (s, CH3), 5.23 (s, 4-H),
6.57-8.16 (m, aromatic H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 21.62 (CH3), 66.82 (C-4), 90.80 (C-5,4’),
124.83-159.73 (C-3 and aromatic C), 168.58 (C=O), 172.06 (C=O) ppm.
(5R*,4:4’R*)-Spiro[3-phenyl-5-(p-tolyl)isoxazoline-4,4’-(2’-phenyl)isoquinoline-1’,3’-dione] (4be):
1
Yield (26%); orange solid; Mp 188 °C; H NMR (300 MHz, CDCl3) δ 2.22 (s, CH3), 6.25 (s, 5-H),
6.78-8.00 (m, aromatic H) ppm; 13C NMR: (75.5 MHz, CDCl3) δ 21.47 (CH3), 97.08 (C-5),70.77 (C-4,4’),
124.19-160.15 (C-3 and aromatic C), 167.75 (C=O), 171.50 (C=O) ppm. Anal. Calcd for C30H22N2O3: C,
78.59; H, 4.84; N, 6.11. Found: C, 78.55; H, 4.76; N, 6.19.
(4S*,5:4’R*)-Spiro[4-(p-anisyl)-3-phenylisoxazoline-5,4’-(2’-phenyl)isoquinoline-1’,3’-dione] (3ce):
1
Yield (58%); white solid; Mp 170 °C; H NMR (300 MHz, CDCl3) δ 3.78 (s, OCH3), 5.21 (s, 4-H),
6.57-8.26 (m, aromatic H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 55.24 (OCH3), 66.20 (C-4), 90.39
(C-5,4’), 114.77-161.23 (C-3 and aromatic C), 168.31 (C=O), 171.67 (C=O) ppm; Anal. Calcd for
C30H22N2O4: C, 75.94; H, 4.67; N, 5.90. Found: C, 75.99; H, 4.77; N, 5.98.
(5R*,4:4’R*)-Spiro[5-(p-anisyl)-3-phenylisoxazoline-4,4’-(2’-phenyl)isoquinoline-1’,3’-dione] (4ce):
1
Yield (21%); orange solid; Mp 207 °C; H NMR (300 MHz, CDCl3) δ 3.84 (s, OCH3), 6.23 (s, 5-H),
6.64-8.32(m, aromatic H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 55.48 (OCH3), 97.00 (C-5), 70.83
(C-4,4’), 115.64-161.78 (C-3 and aromatic C), 166.93 (C=O), 171.52 (C=O) ppm.
(4S*,5:4’R*)-Spiro[4-(p-nitrophenyl)-3-phenylisoxazoline-5,4’-(2’-phenyl)isoquinoline-1’,3’-dione]

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(3de): Yield (65%); orange solid; Mp 212 °C; 1H NMR (300 MHz, CDCl3) δ 5.25 (s, 4-H), 7.05-8.26 (m,
13
aromatic H) ppm; C NMR (75.5 MHz, CDCl3) δ 67.20 (C-4), 90.90 (C-5,4’), 125.50-159.93 (C-3 and
aromatic C), 168.46 (C=O), 172.20 (C=O) ppm.
(5R*,4:4’R*)-Spiro[5-(p-nitrophenyl)-3-phenylisoxazoline-4,4’-(2’-phenyl)isoquinoline-1’,3’-dione]
(4de): Yield (20%); yellow solid; Mp 165 °C; 1H NMR (300 MHz, CDCl3) δ 6.28 (s, 5-H), 7.10-8.20 (m,
13
aromatic H) ppm; C NMR: (75.5 MHz, CDCl3) δ 97.60 (C-5), 70.87 (C-4,4’), 124.64-160.34 (C-3 and
aromatic C), 168.43 (C=O), 171.40 (C=O) ppm; Anal. Calcd for C29H19N3O5: C, 71.16; H, 3.91; N, 8.58.
Found: C, 71.09; H, 3.80; N, 8.65.
(4S*,5:4’R*)-Spiro[4-phenyl-3-(p-tolyl)isoxazoline-5,4’-(2’–phenyl)isoquinoline-1’,3’-dione] (3af):
1
Yield (61%); white solid; Mp 190 °C; H NMR (300 MHz, CDCl3) δ 2.21 (s, CH3), 5.22 (s, 4-H),
6.75-8.00 (m, aromatic H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 21.88 (CH3), 67.11 (C-4), 90.61 (C-5,4’),
125.19-159.25 (C-3 and aromatic C), 164.28 (C=O), 172.03 (C=O) ppm.
(5R*,4:4’R*)-Spiro[5-phenyl-3-(p-tolyl)isoxazoline-4,4’-(2’-phenyl)isoquinoline-1’,3’-dione] (4af):
1
Yield (23%); yellow solid; Mp 210 °C; H NMR (300 MHz, CDCl3) δ 2.22 (s, CH3), 6.19 (s, 5-H),
6.56-7.96 (m, aromatic H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 21.90 (CH3), 96.75 (C-5), 70.90 (C-4,4’),
124.43-159.41 (C-3 and aromatic C), 163.63 (C=O), 171.52 (C=O) ppm.
(4S*,5:4’R*)-Spiro[3-(p-tolyl)-4-(p-tolyl)isoxazoline-5,4’-(2’-phenyl)isoquinoline-1’,3’-dione] (3bf):
1
Yield (60%); colourless solid; Mp 240 °C; H NMR (300 MHz, CDCl3) δ 2.21 (s, CH3), 2.32 (s, CH3),
5.21(s, 4-H), 6.75-8.01 (m, aromatic H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 21.43 (CH3), 21.65 (CH3),
67.00 (C-4), 90.67 (C-5,4’), 124.92-160.30 (C-3 and aromatic C), 164.26 (C=O), 172.09 (C=O) ppm.
Anal. Calcd for C31H24N2O3: C, 78.80; H, 5.12; N, 5.93. Found: C, 78.71; H, 5.23; N, 5.99.
(5R*,4:4’R*)-Spiro[3-(p-tolyl)-5-(p-tolyl)isoxazoline-4,4’-(2’-phenyl)isoquinoline-1’,3’-dione] (4bf):
Yield (25%); yellow solid; Mp 215 °C; 1H NMR (300 MHz, CDCl3) δ 2.23 (s, CH3), 2.34 (s, CH3), 6.16
(s, 5-H), 6.85-8.09 (m, aromatic H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 21.51 (CH3), 21.77 (CH3),
96.94 (C-5), 70.86 (C-4,4’), 124.13-160.09 (C-3 and aromatic C), 163.68 (C=O), 171.54 (C=O) ppm.
(4S*,5:4’R*)-Spiro[4-(p-anisyl)-3-(p-tolyl)isoxazoline-5,4’-(2’-phenyl)isoquinoline-1’,3’-dione] (3cf):
Yield (62%); colourless solid; Mp 230 °C; 1H NMR (300 MHz, CDCl3) δ 2.30 (s, CH3), 3.65 (s, OCH3),
5.20 (s, 4-H), 6.80-8.23 (m, aromatic H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 21.65 (CH3) 55.57 (OCH3)
66.66 (C-4), 90.58 (C-5,4’), 115.07-161.41 (C-3 and aromatic C), 164.33 (C-1), 172.13 (C-2) ppm. Anal.
Calcd for C31H24N2O4: C, 76.21; H, 4.95; N, 5.73. Found: C, 76.15 ; H, 4.86; N, 5.82.
(5R*,4:4’R*)-Spiro[5-(p-anisyl)-3-(p-tolyl)isoxazoline-4,4’-(2’-phenyl)isoquinoline-1’,3’-dione] (4cf):
Yield (21%); orange solid; Mp 195 °C; 1H NMR (300 MHz, CDCl3) δ 2.24 (s, CH3), 3.78 (s, OCH3), 6.12
13
(s, 5-H), 6.55-8.02 (m, aromatic H) ppm; C NMR (75.5 MHz, CDCl3) δ 21.78 (CH3), 55.82 (OCH3),
96.87 (C-5),70.85 (C-4,4’), 114.33-161.58 (C-3 and aromatic C), 163.66 (C=O), 171.57 (C=O) ppm.

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(4S*,5:4’R*)-Spiro[4-(p-nitrophenyl)-3-(p-tolyl)isoxazoline-5,4’-(2’-phenyl)isoquinoline-1’,3’-dione]
1
(3df): Yield (63%); colourless solid; Mp 220 °C; H NMR (300 MHz, CDCl3) δ 2.22 (s, CH3), 5.24 (s,
13
4-H), 6.80-8.10 (m, aromatic H) ppm; C NMR (75.5 MHz, CDCl3) δ 21.76 (CH3), 67.24 (C-4), 90.76
(C-5,4’), 125.64-160.41 (C-3 and aromatic C), 164.20 (C=O), 172.06 (C=O) ppm. Anal. Calcd for
C30H21N3O5: C, 71.56; H, 4.20; N, 8.35. Found: C, 71.50; H, 4.12; N, 8.23.
(5R*,4:4’R*)-Spiro[(5-(p-nitrophenyl)-3-(p-tolyl)isoxazoline-4,4’-(2’-phenyl)isoquinoline-1’,3’-
dione] (4df): Yield (20%); orange solid; Mp 190 °C; 1H NMR (300 MHz, CDCl3) δ 2.23 (s, CH3), 6.22 (s,
13
5-H), 7.01-8.08 (m, aromatic H) ppm; C NMR (75.5 MHz, CDCl3) δ 21.80 (CH3), 96.89 (C-5), 70.94
(C-4,4’), 125.33-160.22 (C-3 and aromatic C), 163.61(C=O), 171.42 (C=O) ppm.
(4S*,5:4’R*)-Spiro[3-(p-anisyl)-4-phenylisoxazoline-5,4’-(2’-phenyl)isoquinoline-1’,3’-dione] (3ag):
1
Yield (62%); white solid; Mp175 °C; H NMR (300 MHz, CDCl3) δ 3.76 (s, OCH3), 5.21 (s, 4-H),
6.75-8.26 (m, aromatic H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 55.69 (OCH3), 67.27 (C-4), 90.57
(C-5,4’), 114.53-161.65 (C-3 and aromatic C), 164.25 (C=O), 172.06 (C=O) ppm.
(5R*,4:4’R*)-Spiro[3-(p-anisyl)-5-phenylisoxazoline-4,4’-(2’-phenyl)isoquinoline-1’,3’-dione] (4ag):
1
Yield (20%); white solid; Mp 220 °C; H NMR (300 MHz, CDCl3) δ 3.80 (s, OCH3), 6.29 (s, 5-H),
6.85-8.07 (m, aromatic H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 55.78 (OCH3), 96.70 (C-5), 70.94
(C-4,4’), 114.64-161.81 (C-3 and aromatic C), 163.58 (C=O), 171.51 (C=O) ppm.
(4S*,5:4’R*)-Spiro[3-(p-anisyl)-4-(p-tolyl)isoxazoline-5,4’-(2’-phenyl)isoquinoline-1’,3’-dione]
1
(3bg): Yield (60%); orange solid; Mp 204 °C; H NMR (300 MHz, CDCl3) δ 2.15 (s, CH3), 3.76 (s,
OCH3), 5.20 (s, 4-H), 6.73-8.25 (m, aromatic H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 21.56 (CH3) 55.67
(OCH3) 67.06 (C-4), 90.57 (C-5,4’), 114.47-161.43 (C-3 and aromatic C), 164.34 (C=O), 172.20 (C=O)
ppm.
(5R*,4:4’R*)-Spiro[3-(p-anisyl)-5-(p-tolyl)isoxazoline-4,4’-(2’-phenyl)isoquinoline-1’,3’-dione]
1
(4bg): Yield (18%); colourless solid; Mp 227 °C; H NMR (300 MHz, CDCl3) δ 2.38 (s, CH3) 3.80 (s,
OCH3), 6.25 (s, 5-H), 6.83-8.10 (m, aromatic H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 21.43 (CH3) 55.79
(OCH3), 96.93 (C-5), 70.92 (C-4,4’), 114.75-161.77 (C-3 and aromatic C), 163.83 (C=O), 171.58 (C=O)
ppm.
(4S*,5:4’R*)-Spiro[3-(p-anisyl)-4-(p-anisyl)isoxazoline-5,4’-(2’-phenyl)isoquinoline-1’,3’-dione]
1
(3cg): Yield (62%); white solid; Mp 236 °C; H NMR (300 MHz, CDCl3) δ 3.76 (s, OCH3), 3.79 (s,
13
OCH3), 5.18 (s, 4-H), 6.55-7.99 (m, aromatic H) ppm; C NMR (75.5 MHz, CDCl3) δ 55.55 (OCH3),
55.68 (OCH3), 66.80 (C-4), 90.53(C-5,4’), 114.53-161.59 (C-3 and aromatic C), 164.31 (C=O), 172.14
(C=O) ppm. Anal. Calcd for C31H24N2O5: C, 73.80; H, 4.79; N, 5.55. Found: C, 73.75; H, 4.72; N, 5.50.
(5R*,4:4’R*)-Spiro[3-(p-anisyl)-4-(p-anisyl)isoxazoline-4,4’-(2’-phenyl)isoquinoline-1’,3’-dione]
1
(4cg): Yield (22%); orange solid; Mp 183 °C; H NMR (300 MHz, CDCl3) δ 3.79 (s, OCH3), 3.80 (s,

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HETEROCYCLES, Vol. 81, No. 3, 2010
OCH3), 6.21(s, 5-H), 6.65-8.10 (m, aromatic H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 55.56 (OCH3),
55.75 (OCH3), 96.83 (C-5), 70.92 (C-4,4’), 114.08-161.77 (C-3 and aromatic C), 163.62 (C=O), 171.57
(C=O) ppm.
(4S*,5:4’R*)-Spiro[3-(p-anisyl)-4-(p-nitrophenyl)isoxazoline-5,4’-(2’-phenyl)isoquinoline-1’,3’-dion]
(3dg): Yield (62%); dark brown solid; Mp 216 °C; 1H NMR (300 MHz, CDCl3) δ 3.76 (s, OCH3), 5.20 (s,
4-H), 6.70-8.30 (m, aromatic H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 55.66 (s, OCH3), 67.38 (C-4),
90.60 (C-5,4’), 114.50-161.71 (C-3 and aromatic C), 164.42 (C=O), 172.09 (C=O) ppm.
(5R*,4:4’R*)-Spiro[3-(p-anisyl)-5-(p-nitrophenyl)isoxazoline-4,4’-(2’-phenyl)isoquinoline-1’,3’-
dione] (4dg): Yield (25%); colourless solid; Mp 186 °C; 1H NMR (300 MHz, CDCl3) δ 3.79 (s, OCH3),
13
6.27 (s, 5-H), 6.80-8.15 (m, aromatic H) ppm; C NMR (75.5 MHz, CDCl3) δ 55.76 (s, OCH3), 96.90
(C-5), 70.97 (C-4,4’), 114.72-161.90 (C-3 and aromatic C), 163.54 (C=O), 171.53 (C=O) ppm. Anal.
Calcd for C30H21N3O6: C, 69.36; H, 4.07; N, 8.09. Found: C, 69.24; H, 3.98; N, 8.03.
ACKNOWLEDGEMENTS
The authors are grateful to DGRSRT (Direction Générale de la Recherche Scientifique et de la
Rénovation Technologique) of the Tunisian Ministry of Higher Education, Scientific Research and
Technology for the financial support. The authors would like to thank Dr. Besma Hamdi (Laboratoire des
Sciences de Matériaux et d'Environnement, Faculté des Sciences de Sfax, Tunisie) for XRD
measurements.
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