HETEROCYCLES

Note | Regular issue | Vol. 81, No. 3, 2010, pp. 707-715
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*

Department of Chemistry, Faculty of Sciences, Laboratoire de Synthèse Organique Asymétrique et Catalyse Homogène, Avenue of the Environment, 5019 Monastir, Tunisia

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 48 h afforded the two regioisomers spiro-isoquinolinoisoxazolines 3ae-dg and 4ae-dg with good chemical yields and comparable ratios as shown in Table1.

During this study, we have submitted dipolarophiles 1a-d to cycloaddition reaction with the arylnitrile oxides 2e-g leading to a mixture of two adducts as evidenced by TLC and 1H 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 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 derivatives.7,10 The 1H NMR spectra of regioisomers 3ae-dg exhibited a signal around δ= 5.18-5.25 ppm attributed to the proton H-4. The 13C 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 of the oxygen atom. In the case of structures 4ae-dg, the 1H 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.

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 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 Kα (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 Kα (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).
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) ppm; 13C 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): Yield (59%); white solid; Mp 230 °C; 1H 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): Yield (26%); orange solid; Mp 188°C; 1H 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): Yield (58%); white solid; Mp 170 °C; 1H 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): Yield (21%); orange solid; Mp 207 °C; 1H 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] (3de): Yield (65%); orange solid; Mp 212 °C; 1H NMR (300 MHz, CDCl3) δ 5.25 (s, 4-H), 7.05-8.26 (m, aromatic H) ppm; 13C 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, aromatic H) ppm; 13C 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): Yield (61%); white solid; Mp 190 °C; 1H 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): Yield (23%); yellow solid; Mp 210 °C; 1H 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): Yield (60%); colourless solid; Mp 240 °C; 1H 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 (s, 5-H), 6.55-8.02 (m, aromatic H) ppm; 13C 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.
(4S*,5:4’R*)-Spiro[4-(p-nitrophenyl)-3-(p-tolyl)isoxazoline-5,4’-(2’-phenyl)isoquinoline-1’,3’-dione] (3df): Yield (63%); colourless solid; Mp 220 °C; 1H NMR (300 MHz, CDCl3) δ 2.22 (s, CH3), 5.24 (s, 4-H), 6.80-8.10 (m, aromatic H) ppm; 13C 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, 5-H), 7.01-8.08 (m, aromatic H) ppm; 13C 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): Yield (62%); white solid; Mp175 °C; 1H 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): Yield (20%); white solid; Mp 220 °C; 1H 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] (3bg): Yield (60%); orange solid; Mp 204 °C; 1H 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] (4bg): Yield (18%); colourless solid; Mp 227 °C; 1H 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] (3cg): Yield (62%); white solid; Mp 236 °C; 1H NMR (300 MHz, CDCl3) δ 3.76 (s, OCH3), 3.79 (s, OCH3), 5.18 (s, 4-H), 6.55-7.99 (m, aromatic H) ppm; 13C 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] (4cg): Yield (22%); orange solid; Mp 183 °C; 1H NMR (300 MHz, CDCl3) δ 3.79 (s, OCH3), 3.80 (s, 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), 6.27 (s, 5-H), 6.80-8.15 (m, aromatic H) ppm; 13C 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.

References

1. N. Uenver, T. Goezler, N. Walch, B. Goezler, and M. Hesse, Phytochemistry, 1999, 50, 1255; CrossRef G. Grethe, ‘Isoquinolines Part 1: In the series Chemistry of Heterocyclic Compounds Vol. 38’, ed. by A. Weissberger and E. C. Taylor, Wiley, New York, 1981. pp. 1-4.
2. D. A. Carper, T. C. Hohman, and S. E. Old, Biochim. Biophys. Acta, 1995, 1246, 67; M. S. Malamas and T. C. Hohman, J. Med. Chem., 1994, 37, 2059. CrossRef
3. J. P. Hoelck, W. Kampe, A. Mertens, B. Mueller-Bekmann, and K. Strein, Ger. Offen DE Pat.3410168 (Chem. Abstr.,1986, 104, 50877).
4. V. M. Kisel, E. O. Kostyrko, and V. A. Kovtunenko, Chem. Heterocycl. Compd., 2002, 38, 1295; CrossRef T. Yashiro, K. Yamada, and H. Shirai, Chem. Pharm. Bull.,1975, 23, 2054; S. Chiavarelli, F. Rabagliati, and G. Settimj, Gazz. Chim. Ital., 1960, 90, 189; J. C. Gramain, S. Mavel, Y. Troin, D. Vallee-Goyet, Tetrahedron, 1991, 47, 7301; CrossRef S. S. Huybrechts and G. J. Hoornaert, Synth. Commun.,1981, 11, 17. CrossRef
5. L. Capuano and C. Wamprecht, Liebigs Ann. Chem., 1986, 5, 938; CrossRef F. Ponticelli and P. Teedeschi, Heterocycles, 1983, 20, 1315; CrossRef A. Bahloul, S. Kitane, and M. Soufiaoui, J. Soc. Maroc. Chim., 1993, 2, 12.
6. J. C. Gramain, Y. Troin, and D. Vallee, J. Chem. Soc., Chem. Commun., 1981, 16, 832; CrossRef H. Kagi and K. Miescher, Helv. Chim. Acta, 1949, 32, 2489. CrossRef
7. M. Askri, N. Jegham, M. Rammah, K. Ciamala, K. M. Jobé, and J. Vebrel, Heterocycles, 2007, 71, 289. CrossRef
8. A. S. Bailey, A. P. Ledger, and N. R. D. Perkins, J. Chem. Soc., C, 1967, 323; CrossRef H. Kubota, A. Kakefuda, H. Nagaoka, O. Yamamoto, K. Ikeda, M. Takeuchi, T. Shibanuma, and Y. Isomura, Chem. Pharm. Bull., 1998, 46, 242.
9. K. C. Liu, R. B. Shelton, and R. K. Howe, J. Org. Chem., 1980, 45, 3916; CrossRef C. Grundman and R. Richter, J. Org. Chem., 1967, 32, 2308; CrossRef R. Huisgen and N. Mack, Tetrahedron Lett., 1961, 2, 583; CrossRef R. H. Wiley and B. J. Wakefield, J. Org. Chem., 1960, 25, 546; CrossRef Y. H. Chiang, J. Org. Chem., 1971, 36, 2146. CrossRef
10. S. Manikandan, M. Shanmugasundarm, R. Raghunathan, and E. J. Padma Malar, Heterocycles, 2000, 53, 579; CrossRef R. Fihi, K. Ciamala, J. Vebrel, and N. Rodier, Bull. Soc. Chim. Belg., 1995, 104, 55.
11. D. E. Horning, G. Lacasse, and L. M. Muchowski, Can. J. Chem., 1971, 49, 246. CrossRef