Scientific paper
1,3-Dipolar Cycloaddition Reactions of ^-Methyl-Substituted Tricyclic Imides
Gokce Goksu and Nuket Ocal*
Yildiz Technical University, Faculty of Science and Arts, Davutpasa Campus, 34210 Esenler-Istanbul, Turkey
* Corresponding author: E-mail: nocal@yildiz.edu.tr Tel.:+90-2123834214
Received: 11-10-2010
Abstract
The [3+2] cycloadditions of N-methyl derivatives of unsaturated imides with various nitrile oxides to yield new bridged isoxazoline derivatives with potential biological activity is described.
Keywords: Alkenes, cycloadditions, heterocycles, triyclic imides, cantharidin analogues
1. Introduction
Cycloaddition reactions are among the most powerful methods for the construction of rings.1 The 1,3-dipolar cycloaddition of nitrile oxides to alkenes is a widely used, efficient method for the synthesis of isoxazolines.2 Isoxa-zolines are versatile intermediates for the synthesis of a variety of bioactive compounds and possess a broad spectrum of biological activity such as insecticidal, antibacterial, antibiotic, antitumor and antifungal.3-5 The isoxazoli-ne ring has been revealed to be a latent precursor for a variety of difunctional compounds, like y-amino alcohols, 0-hydroxy ketones, 0-hydroxy nitriles and unsaturated oxi-mes, therefore this heterocycle has been utilized for construction of natural products having such functionali-ties.6,7
In addition, N-substituted imides, such as maleimi-des,8 isohematinic acids9 and especially bicyclic and tricyclic derivatives such as tandospirone derivatives10,11 are known for their broad spectrum of pharmacological properties, thus showing antibiotic, fungicidal, analgesic, anxiolytic and cytostatic effects. The imide moiety is an integral structural part of various important bioactive molecules such as fumaramidmycin, granulatimide, isogranulatimide and rebeccamycin. These molecules are reported to exhibit antitumor, anti-inflammatory and antimicrobial activities.12,13 A literature search reveals that certain compounds with antitumor activity, and in particular molecules able to interact with DNA, are characterized by the presence of both an extended n-system and an imide func-
tion. Apart from biological activities, imide derivatives are useful in the reactions involving condensations, alkyla-tions, acylations and cyclocondensations.
On the other hand, the intramolecular cycloaddition is useful synthetic strategy to yield bicyclic and tricyclic compounds, often proceeding with high regio- and stereoselectivity. Derivatives of the tricyclic anhydride exo-5,6-dehydronorcantharidin are also pharmacologically active. Hu and Deng had studied the reactions of 5,6-dehydronor-cantharidin derivatives with three types of nitrile oxides and found that they are active against HL60 cells, but only in high concentration.14 Recently, we were interested in the intramolecular cycloaddition of aryl and heteroaryl substituted tricyclic hydrazones with nitrile oxides because of possible bioactive compounds.15 In this paper, we describe the synthesis of various tetracyclic isoxazolines (via 1,3-dipolar cycloaddition) as new representatives of 5,6-dehydronorcantharidin derivatives.
2. Results and Discussion
Our synthesis started with the Diels-Alder reaction of cyclopentadiene and N-methylmaleimide. The reaction occurred in dry benzene under reflux to give N-methyl-bicyclo[2.2.1]hept-8-ene-3,endo-5-endo-dicarboximide (1) as colorless crystals (yield 93%).16 The same reaction was successfully applied to the reaction of furan with N-methylmaleimide to give both diastereomers, the N-methyl-10-oxabicyclo[2.2.1]hept-8-ene-3,endo-5-endo-
dicarboximide (endo-2) and V-methyl-10-oxabicyc-lo[2.2.1]hept-8-ene-3,exo-5-exo-dicarboximide (exo-2) in good yields after chromatographic separation.17 We also synthesized 3 from 1,3-cyclohexadiene with V-methylma-leimide under the similar conditions (Scheme 1).16
Norbornene and its derivatives have figured prominently in organic chemistry. The presence of a rigid bicyclic skeleton gives rise to stereoisomers with fixed spatial orientation of substitutents. The double bond in substituted norbornenes is quite reactive toward cycloadends, in particular toward nitrile oxides in 1,3-dipolar cycloadditions. We carried out the [3+2] cycloaddition of 1 and exo-2 with 2-chlorophenyl nitri-le oxide (generated in situ from 2-chlorobenzaldehyde oxime with NaOCl), to obtain the target compounds 4 and 13. The same conditions were successfully applied to the reactions of endo-2 and 3 with 4-chlorobenzal-deyde oxime to give the new heterocycles 7 and 10 in good yields after chromatographic separation. Analogously, compounds 8, 11 and 14 were obtained from endo-2, exo-2 and 3 with 2,5-dimethoxybenzaldehyde oxime, respectively, and compound 5 was prepared from 1 with 2,4-dimethylbenzaldehyde oxime (Scheme 2).
We also synthesized 6, 9, 12 and 15 from 1-3 with 2-thiophencarbaldehyde oxime prepared as new isoxazo-lines under the 1,3-dipolar cycloaddition conditions (Scheme 2).
The 1H NMR spectra of 4-15 are in accord with the proposed structures. In order to identify the configuration of the isoxazolines with tricyclic imide adducts we have
studied selective 1H-1H-COSY spectra obtained from these compounds. 1H-1H-COSY spectra show the cross peaks between resonances for H4a and H7a; H3an and H8an. The MS/EI spectra of cycloadducts 4-15 showed the characteristic molecular ion peaks.
3. Experimental
Reactions were monitored by thin-layer chromatography (TLC). Visualization of the developed chromato-grams was performed either with UV light or KMnO4 stain. Products were purified by silica gel chromatography with a solvent gradient of ethyl acetate/n-hexane to afford the title compounds. IR spectra were obtained with a Per-kin Elmer, FT-IR instrument and absorption frequencies are reported in cm-1. Melting points were determined with a Gallenkamp digital thermometer. All NMR spectra were determined with a Varian-INOVA-500 spectrometer. TMS (tetramethylsilane) was used as internal standard and CDCl3 as the solvent. Mass spectra were measured with Agilent 6890N GC-System-5973 IMSD and Agilent 6460-A model LC-Triple Quadrupole MS/MS system (Jet Stream Electro spray ionization source).
3. 1. General Procedure for Preparing Isoxazolines 4-15
Olefin (1 mmol) and aldoxime (1 mmol) were dissolved in CH2Cl2 and the solution was cooled to 0 °C. NaOCl (10-13%) was added dropwise to the stirring solution. The biphasic mixture was allowed to warm to room temperature and was stirred for 8 h. An additional volume of water was added and the layers were separa-
Scheme 2. General synthesis of compounds 4-15
ted. The aqueous layer was extracted two to three additional times with CH2Cl2, and the combined organic layers were dried with MgSO4, evaporated under vacuum and purified by column chromatography to give the product.
4,8-Methano-3-(2-chlorophenyl)-6-methyl-4,4a,8,exo-8a-tetrahydro-exo-3aH-isoxazolo[5,4-/]isoindole-5,7 (6H,7aH)-endo-dione (4). Colorless solid, yield 92%, mp 200-204 °C. 1H NMR (500 MHz, CDCl3) 5 1.54 (d, J = 11.1 Hz, 1H, H-9s), 1.82 (d, J = 11.1 Hz, 1H, H-9a), 2.69 (brs, 1H, H-4), 2.94 (s, 3H, N-CH3), 3.08 (brs, 1H, H-8), 3.10-3.12 (m, 2H, H-4a and H-7a), 3.82 (d, J = 8.4 Hz, 1H, H-3an), 4.56 (d, J = 8.4 Hz, 1H, H-8an), 7.22 (dd, J1 = J2 = 8.7 Hz, 1H, ArH), 7.29 (dd, J1 = J2 = 8.7 Hz, 1H, ArH), 7.37 (d, J = 8.7 Hz, 1H, ArH), 7.42 (d, J = 8.7 Hz,
1H, ArH). 13C NMR (125 MHz, CDCl3) 5 24.74 (N-CH3), 36.04 (C-9), 41.32 (C-4), 44.65 (C-8), 45.57 (C-4a), 46.73 (C-7a), 54.63 (C-3a), 83.08 (C-8a), 127.09 (ArC), 127.38 (ArC), 130.86 (ArC), 130.90 (ArC), 131.11 (ArC), 132.92 (ArC), 156.09 (C-3), 176.10 (C-7), 176.51 (C-5). IR (ATR) v 2992, 2959, 1765 (C=O), 1690 (C=O), 1591, 1462, 1427, 1374, 1347, 1276, 1133, 1113, 977, 905, 867, 771 cm-1. GC-MS (EI, 70 eV) m/z 330 (M+), 295, 206, 192, 178, 111, 66.
4,8-Methano-3-(2,4-dimethylphenyl)-6-methyl-4,4a,8,exo-8a-tetrahydro-exo-3aH-isoxazolo[5,4-/] isoindole-5,7(6H,7aH)-endo-dione (5). Colorless solid, yield 53%, mp 165-169 °C. 1H NMR (500 MHz, CDCl3) 5 1.58 (d, J = 11.1 Hz, 1H, H-9s), 1.86 (d, J = 11.1 Hz, 1H, H-9a), 2.36 (s, 3H, CH3), 2.50 (s, 3H, CH3), 2.90-2.92 (m, 1H, H-4), 3.05 (s, 3H, N-CH3), 3.16-3.19 (m, 1H, H-8), 3.20-3.23 (m, 2H, H-4a and H-7a), 3.64 (d, J = 8.3 Hz, 1H, H-3an), 4.53 (d, J = 8.3 Hz, 1H, H-8an), 7.07-7.12 (m, 2H, ArH), 7.25 (d, J = 7.7 Hz, 1H, ArH). 13C NMR (125 MHz, CDCl3) 5 21.21 (CH3), 23.36 (CH3), 24.74 (N-CH3), 36.09 (C-9), 41.83 (C-4), 44.59 (C-8), 45.80 (C-4a), 46.89 (C-7a), 54.89 (C-3a), 81.54 (C-8a), 124.12 (ArC), 126.84 (ArC), 128.91 (ArC), 132.75 (ArC), 138.48 (ArC), 139.77 (ArC), 157.04 (C-3), 176.27 (C-7), 177.00 (C-5). IR (ATR) v 2976, 2942, 1770 (C=O), 1696
(C=O), 1585, 1431, 1380, 1276, 1130, 1037, 983, 942, 921, 896, 869, 816 cm-1; GC-MS (EI, 70 eV) m/z 324 (M+), 309, 295, 281, 236, 191, 66.
4,8-Methano-3-(2-thienyl)-6-methyl-4,4a,8,exo-8a-te-trahydro-exo-3aH-isoxazolo[5,4-/]isoindole-5,7(6H, 7aH)-endo-dione (6). Colorless solid, yield 60%, mp 245-248 °C. 1H NMR (500 MHz, CDCl3) 5 1.55 (d, J = 10.7 Hz, 1H, H-9s), 1.81 (d, J = 10.7 Hz, 1H, H-9a), 2.94 (s, 3H, N-CH3), 3.03 (brd, J = 4.8 Hz, 1H, H-4), 3.09 (brd, J = 4.8 Hz, 1H, H-8), 3.12-3.19 (m, 2H, H-4a and H-7a), 3.41 (d, J = 6.8 Hz, 1H, H-3an), 4.53 (d, J = 6.8 Hz, 1H, H-8an), 6.99 (dd, J1 = 4.2 Hz, J2 = 5.6 Hz, 1H, ArH), 7.18 (dd, J1 = 0.9 Hz, J2 = 3.9 Hz, 1H, ArH), 7.32 (dd, J1 = 0.9 Hz, J2 = 3.9 Hz, 1H, ArH). 13C NMR (125 MHz, CDCl3) 5 24.92 (N-CH3), 36.32 (C-9), 42.40 (C-4), 44.62 (C-8), 45.64 (C-4a), 437.08 (C-7a), 53.95 (C-3a), 83.62 (C-8a), 127.71 (ArC), 128.77 (ArC), 128.86 (ArC), 130.92 (ArC), 152.42 (C-3), 176.22 (C-7), 176.98 (C-5). IR (ATR) v 3103, 2976, 1769, 1676, 1429, 1377, 1357, 1274, 1130, 1120, 1077, 981, 916, 837, 808 cm-1; GC-MS (EI, 70 eV) m/z 302 (M+), 163, 66.
4,8-Epoxy-3-(4-chlorophenyl)-6-methyl-4,4a,8,exo-8a-tetrahydro-exo-3aH-isoxazolo[5,4-/]isoindole-5,7(6H, 7aH)-endo-dione (7). Colorless solid, yield 65%, mp 267-269 °C. 1H NMR (500 MHz, CDCl3) 5 2.97 (s, 3H, N-CH3), 3.47-3.53 (m, 2H, H-4a and H-7a), 3.79 (d, J = 7.8 Hz, 1H, H-3an), 4.80 (d, J = 7.8 Hz, 1H, H-8an), 4.89 (d, J = 5.8 Hz, 1H, H-4), 5.08 (d, J = 5.8 Hz, 1H, H-8), 7.34 (d, J = 8.7 Hz, 2H, ArH), 7.50 (d, J = 8.7 Hz, 1H, ArH). 13C NMR (125 MHz, CDCl3) 5 25.38 (N-CH3), 47.76 (C-4a), 50.13 (C-7a), 55.10 (C-3a), 79.38 (C-8a), 83.48 (C-4), 83.77 (C-8), 126.42 (ArC), 128.22 (ArC), 129.65 (ArC), 136.89 (ArC), 153.76 (C-3), 173.68 (C-7), 174.63 (C-5). IR (ATR) v 3063, 2925, 2850, 1769 (C=O), 1693 (C=O), 1595, 1493, 1435, 1379, 1354, 1277, 1136, 1092, 994, 890, 831, 819 cm-1; GC-MS (EI, 70 eV) m/z 332 (M+), 178, 153, 137, 111, 68.
4,8-Epoxy-3-(2,5-dimethoxyphenyl)-6-methyl-4,4a,8, exo-8a-tetrahydro-exo-3aH-isoxazolo[5,4-/]isoindole-5,7(6H,7aH)-endo-dione (8). Colorless solid, yield 60%, mp 221-222 °C. 1H NMR (500 MHz, CDCl3) 5 2.95 (s, 3H, N-CH3), 3.43-3.45 (m, 2H, H-4a and H-7a), 3.70 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.14 (d, J = 8.7 Hz, 1H, H-3an), 4.72 (d, J = 8.7 Hz, 1H, H-8an), 4.82 (brd, J = 3.9 Hz, 1H, H-4), 5.01 (brd, J = 3.9 Hz, 1H, H-8), 6.82 (d, J = 8.7 Hz, 1H, ArH), 6.89 (dd, J1 = 2.9 Hz, J2 = 8.7 Hz, 1H, ArH), 7.40 (d, J = 2.9 Hz, 1H, ArH). 13C NMR (125 MHz, CDCl3) 5 25.24 (N-CH3), 48.00 (C-4a), 50.11 (C-7a), 55.93 (C-3a), 56.00 (OCH3), 57.41 (OCH3), 80.38 (C-8a), 83.01 (C-4), 83.57 (C-8), 112.90 (ArC), 113.20 (ArC), 116.65 (ArC), 119.32 (ArC), 151.53 (ArC), 153.84 (ArC), 153.93 (C-3), 174.13 (C-7), 174.32 (C-5). IR (ATR) v 3020, 2957, 2835, 1781 (C=O), 1692 (C=O), 1563, 1491,
1462, 1445, 1427, 1376, 1337, 1294, 1268, 1213, 1186, 1129, 1041, 1011, 921, 893, 796 cm-1; GC-MS (EI, 70 eV) m/z 358 (M+), 329, 301, 190, 176, 163, 148, 68.
4,8-Epoxy-3-(2-thienyl)-6-methyl-4,4a,8,exo-8a-tetrah ydro-exo-3aH-isoxazolo[5,4-/]isoindole-5,7(6H,7aH)-endo-dione (9). Colorless solid, yield 50%, mp 267-269 °C. 1H NMR (500 MHz, CDCl3) 5 2.96 (s, 3H, N-CH3), 3.46-3.53 (m, 2H, H-4a and H-7a), 3.78 (d, J = 7.8 Hz, 1H, H-3an), 4.78 (d, J = 7.8 Hz, 1H, H-8an), 5.03 (d, J = 5.8 Hz, 1H, H-4), 5.08 (d, J = 5.8 Hz, 1H, H-8), 7.02 (dd, J1 = 3.4 Hz, J2 = 4.8 Hz, 1H, ArH), 7.16 (dd, J1 = 0.9 Hz, J2 = 3.4 Hz, 1H, ArH), 7.35 (dd, J1 = 0.9 Hz, J2 = 4.8 Hz, 1H, ArH). 13C NMR (125 MHz, CDCl3) 5 24.13 (N-CH3), 46.47 (C-4a), 48.85 (C-7a), 55.05 (C-3a), 78.38 (C-8a), 82.15 (C-4), 82.46 (C-8), 126.51 (ArC), 127.35 (ArC), 128.05 (ArC), 129.31 (ArC), 149.35 (C-3), 172.47 (C-7), 173.25 (C-5). IR (ATR) v 3104, 2981, 1776 (C=O), 1691 (C=O), 1585, 1436, 1423, 1337, 1276, 1226, 1132, 1060, 1034, 997, 921, 734 cm-1; GC-MS (EI, 70 eV) m/z 304 (M+), 275, 247, 164, 136, 109, 84, 68.
0
4,8-Ethano-3-(4-chlorophenyl)-6-methyl-4,4a,8,exo-8a -tetrahydro-exo-3aH-isoxazolo[5,4-/jisoindole-5,7(6H, 7aH)-endo-dione (10). Colorless solid, yield 57%, mp 240 °C. 1H NMR (500 MHz, CDCl3) 5 1.30-1.41 (m, 3H, H-10s, H-9a and H-9s), 1.94-2^3 (m, 1H, H-10a), 2.57-2.60 (m, 1H, H-4), 2.63-2.65 (m, 1H, H-8), 2.91 (dd, J1 = 3.9 Hz, J2 = 9.2 Hz, 1H, H-4a), 2.97 (dd, J1 = 3.9 Hz, J2 = 9.2 Hz, 1H, H-7a), 3.00 (s, 3H, N-CH3), 3.43 (ddd, J1 = 1.4 Hz, J2 = 3.4 Hz, J3 =11.7 Hz, 1H, H-3an), 4.55 (dd, J1 = 3.4 Hz, J2 = 11.7 Hz, 1H, H-8an), 7.31 (d, J = 8.7 Hz, 2H, ArH), 7.49 (d, J = 8.7 Hz, 2H, ArH). 13C NMR (125 MHz, CDCl3) 5 17.45 (C-9), 20.33 (C-10), 25.17 (N-CH3), 27.48 (C-4), 29.53 (C-8), 40.90 (C-4a), 42.46 (C-7a), 46.73 (C-3a), 78.53 (C-8a), 127.29 (ArC), 128.15 (ArC), 129.52 (ArC), 136.56 (ArC), 156.18 (C-3), 178.19 (C-7), 178.82 (C-5). IR (ATR) v 3053, 2954, 2926, 1764 (C=O), 1675 (C=O), 1591, 1492, 1436, 1387, 1282, 1129, 1092, 1014, 974, 917, 891, 826 cm-1; GC-MS (EI, 70 eV) m/z 344 (M+), 327, 232, 178, 113, 96, 79.
4,8-Ethano-3-(2,5-dimethoxyphenyl)-6-methyl-4,4a,8, exo-8a-tetrahydro-exo-3aH-isoxazolo[5,4-/]isoindole-
5,7(6H,7aH)-endo-dione (11). Colorless solid, yield 63%, mp 175-177 °C. NMR (500 MHz, CDCl3) 5 1.23-1.33 (m, 2H, H-10s and H-9s), 1.37-1.43 (m, 1H, H-9a), 1.96-2.02 (m, 1H, H-10a), 2.37-2.40 (m, 1H, H-4), 2.57-2.61 (m, 1H, H-8), 2.82 (dd, 1H, J1 = 3.9 Hz, J2 = 9.2 Hz, H-4a), 2.92 (dd, 1H, J1 = 3.9 Hz, J2 = 9.2 Hz, H-7a), 2.98 (s, 3H, N-CH3), 3.72 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.82 (brd, 1H, J = 12.2 Hz, H-3an), 4.50 (dd, 1H, J2 = 3.9 Hz, J2 = 12.2 Hz, H-8an), 6.87 (dd, 1H, J2 = 2.9 Hz, J2 = 8.7 Hz, ArH), 6.79 (d, 1H, J = 8.7 Hz, ArH), 7.27 (d, 1H, J = 2.9 Hz, ArH). 13C NMR (125 MHz, CDCl3) 5
17.45	(C-9), 20.84 (C-10), 25.06 (N-CH3), 27.51 (C-4), 29.79 (C-8), 41.42 (C-4a), 42.79 (C-7a), 48.35 (C-3a), 56.06 (OCH3), 56.07 (OCH3), 78.28 (C-8a), 113.07 (ArC), 113.79 (ArC), 118.20 (ArC), 123.60 (ArC), 151.86 (ArC), 153.84 (ArC), 157.15 (C-3), 178.55 (C-7), 178.81 (C-5). IR (ATR) v 3012, 2951, 2918, 2876, 1774 (C=O), 1690 (C=O), 1557, 1493, 1428, 1377, 1275, 1223, 1123, 1043, 1014, 907, 817 cm-1; GC-MS (EI, 70 eV) m/z 370 (M+), 339, 190, 176, 148, 79.
4,8-Ethano-3-(2-thienyl)-6-methyl-4,4a,8,exo-8a-tetra-hydro-exo-3aH-isoxazolo[5,4-/]isoindole-5,7(6H, 7aH)-endo-dione (12). Pale yellow solid, yield 45%, mp 166-170 °C. 1H NMR (500 MHz, CDCl3) 5 1.33-1.37 (m, 2H, H-9s and H-10s), 1.45-1.53 (m, 1H, H-9a), 1.98-2.03 (m, 1H, H-10a), 2.62-2.64 (m, 1H, H-4), 2.70-2.72 (m, 1H, H-8), 2.92 (dd, J2 = 3.9 Hz, J2 = 9.2 Hz, 1H, H-4a), 2.97 (dd, J2 = 3.9 Hz, J2 = 9.2 Hz, 1H, H-7a), 2.98 (s, 3H, N-CH3), 3.40 (brd, J =11.7 Hz, 1H, H-3an), 4.53 (dd, J2 = 3.9 Hz, J2 = 11.7 Hz, 1H, H-8an), 6.98 (dd, J2 = 3.9 Hz, J2 = 4.8 Hz, 1H, ArH), 7.14 (d, J = 3.9 Hz, 1H, ArH), 7.31 (d, J = 4.8 Hz, 1H, ArH). 13C NMR (125 MHz, CDCl3) 5
17.46	(C-9), 20.34 (C-10), 25.17 (N-CH3), 28.06 (C-4), 29.50 (C-8), 40.91 (C-4a), 42.45 (C-7a)3, 47.99 (C-3a), 78.56 (C-8a), 127.71 (ArC), 128.19 (ArC), 128.57 (ArC), 131.21 (ArC), 152.93 (C-3), 178.24 (C-7), 178.80 (C-5). IR (ATR) v 3096, 2948, 2922, 2877, 1767 (C=O), 1690 (C=O), 1520, 1432, 1377, 1278, 1215, 1129, 1091, 972, 911, 838 cm-1; GC-MS (EI, 70 eV) m/z 316 (M+), 151, 113, 96, 79.
4,8-Epoxy-3-(2-chlorophenyl)-6-methyl-4,4a,8,exo-8a-tetrahydro-exo-3aH-isoxazolo[5,4-/]isoindole-5,7(6H, 7aH)-exo-dione (13). Colorless solid, yield 75%, mp 125-128 °C. 1H NMR (500 MHz, CDCl3) 5 2.96 (s, 3H, N-CH3), 3.01 (d, J = 6.9 Hz, 1H, H-4a), 3.05 (d, J = 6.9 Hz, 1H, H-7a), 4.46 (d, J = 8.2 Hz, 1H, H-3an), 4.70 (s, 1H, H-4), 5.05 (d, J = 8.2 Hz, 1H, H-8an), 5.10 (s, 1H, H-8), 7.33 (dd, J2= J2 = 8.7 Hz, 1H, ArH), 7.42 (dd, J2 = J2 = 8.7 Hz, 1H, ArH), 7.47 (d, J = 8.7 Hz, 1H, ArH), 7.52 (d, J = 8.7 Hz, 1H, ArH). 13C NMR (125 MHz, CDCl3) 5 25.42 (N-CH3), 44.99 (C-4a), 48.22 (C-7a), 59.51 (C-3a), 79.56 (C-8a), 84.52 (C-4), 85.63 (C-8), 127.18 (ArC), 127.42 (ArC), 130.54 (ArC), 131.55 (ArC), 131.57 (ArC), 132.49 (ArC), 154.35 (C-3), 175.67 (C-7), 177.59
(C-5). IR (ATR) v 3077, 1771 (C=O), 1689 (C=O), 1474, 1430, 1380, 1345, 1287, 1174, 1134, 1082, 1040, 1018, 906, 877, 846, 822, 756 cm-1; GC-MS (EI, 70 eV) m/z 332 (M+), 303, 275, 241, 193, 178, 111, 68.
4,8-Epoxy-3-(2,5-dimethoxyphenyl)-6-methyl-4,4a,8, exo-8a-tetrahydro-exo-3aH-isoxazolo[5,4-/]isoindole-5,7(6H,7aH)-exo-dione (14). Colorless solid, yield 64%, mp 186-188 °C. 1H NMR (500 MHz, CDCl3) 5 2.87 (d, J = 6.8 Hz, 1H, H-4a), 2.89 (s, 3H, N-CH3), 2.93 (d, J = 6.8 Hz, 1H, H-7a), 3.69 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 4.24 (d, J = 8.3 Hz, 1H, H-3an), 4.76 (s, 1H, H-4), 4.86 (d, J = 8.3 Hz, 1H, H-8an), 4.98 (s, 1H, H-8), 6.84 (d, J = 8.7 Hz, 1H, ArH), 6.90 (dd, J2 = 2.9 Hz, J2 =
8.7	Hz, 1H, ArH), 7.24 (d, J = 2.9 Hz, 1H, ArH). -3C NMR (125 MHz, CDCl3) 5 25.54 (N-CH3), 45.38 (C-4a), 48.79 (C-7a), 56.03 (C-3a), 56.40 (OCH3), 60.16 (OCH3), 80.79 (C-8a), 84.51 (C-4), 85.62 (C-83), 113.29 (ArC), 113.82 (ArC), 117.21 (ArC), 118.79 (ArC), 151.51 (ArC), 153.98 (ArC), 154.00 (C-3), 175.75 (C-7), 175.94 (C-5). IR (ATR) v 3012, 2949, 2832, 1771 (C=O), 1694 (C=O), 1558, 1496, 1465, 1436, 1421, 1386, 1345, 1262, 1224, 1140, 1062, 1021, 992, 910, 847, 807 cm-1; GC-MS (EI, 70 eV) m/z 358 (M+), 329, 207, 179, 163, 148, 68.
4,8-Epoxy-3-(2-thienyl)-6-methyl-4,4a,8,exo-8a-te-trahydro-exo-3aH-isoxazolo[5,4-/]isoindole-5,7(6H, 7aH)-exo-dione (15). Pale yellow solid, yield 48%, mp 205-210 °C. 1H NMR (500 MHz, CDCl3) 5 2.88 (d, J =
6.8	Hz, 1H, H-4a), 2.91 (s, 3H, N-CH3), 3.02 (d, J = 6.8 Hz, 1H, H-7a), 3.90 (d, J = 8.0 Hz, 1H, H-3an), 4.93 (d, J = 8.0 Hz, 1H, H-8an), 5.02 (s, 1H, H-4), 5.05 (s, 1H, H-8), 7.04 (dd, J2 = 3.6 Hz, J2 = 4.9 Hz, 1H, ArH), 7.24 (d, J = 3.6 Hz, 1H, ArH), 7.37 (d, J = 4.9 Hz, 1H, ArH). 13C NMR (125 MHz, CDCl3) 5 25.65 (N-CH3), 45.15 (C-4a), 48.76 (C-7a), 58.17 (C-3a), 80.11 (C-8a), 84.72 (C-4), 86.05 (C-8), 127.72 (ArC), 128.32 (ArC), 128.65 (ArC), 131.11 (ArC), 153.57 (C-3), 175.38 (C-5), 175.69 (C-7). IR (ATR) v 3080, 2924, 2854, 1777 (C=O), 1695 (C=O), 1434, 1385, 1286, 1215, 1132, 1031, 1007, 901, 875, 842 cm-1; GC-MS (EI, 70eV) m/z 304 (M+), 221, 191, 163, 136, 109, 68.
4. Conclusion
We first synthesized N-methylsubstituted adducts 1-3 of the unsaturated imides by a hydroarylation procedure to check the effect on both, the reactivity of the starting materials as well as the bioactivity of the products as Cantharidin analogues.18 In this work, our results have also demonstrated that the 1,3-dipolar cycloadditions of ni-trile oxides onto bridged cyclic imide derivatives prove useful for the construction of novel heterocycles of potential pharmacological interest.
5. Acknowledgements
We gratefully acknowledge financial support of this work by the Yildiz Technical University Scientific Research Projects Coordination Department (Project No. 2801-02-04).
6. References
1.	M. Lautens, W. Klute, W. Tam, Chem. Rev. 1996, 96, 49-92.
2.	P. Caramella, P. Gruenanger, in: 1,3-Dipolar Cycloaddition Chemsitry, A. Padwa (Ed.), Wiley Interscience, New York, 1984, Vol. 1.
3.	K. B. Umesha, K. A. Kumar, K. M. L. Rai, Synth. Commun. 2002, 32, 1841-1846.
4.	G. A. Houari, A. Kerbal, B. Bennani, M. F. Baba, M. Daou-di, T. B. Hadda, Arkivoc 2008, (xii), 42-50.
5.	B. Jayashankara, K. M. L. Rai, Arkivoc 2008, (xi), 75-85.
6.	M. C. P. Yeh, C. F. Jou, W. T. Yeh, D. Y. Chiu, N. R. K. Reddy, Tetrahedron 2005, 61, 493-500.
7.	L. Kiss, M. Nonn, E. Forro, R. Sillanpää, F. Fülöp, Tetrahedron Lett. 2009, 50, 2605-2608.
8.	F. Zentz, A. Valla, R. Le Guillou, R. Labia, A. Mathot, D. Sirot, Il Farmaco 2002, 57, 421-426.
9.	R. M. DiPardo, M. A. Patane, R. C. Newton, R. Price, T. P. Broten, R. S. L. Chang, R. W. Ransom, J. Di Salvo, R. M. Freidinger, M. G. Bock, Bioorg. Med. Chem. Lett. 2001, 11, 1959-1962.
10.	J. Kossakowski, M. Jarocka, Il Farmaco 2001, 56, 785-789.
11.	J. Kossakowski, A. Bielenica, B. Miroslaw, A. E. Koziol, I. Dybala, M. Struga, Molecules 2008, 13, 1570-1583.
12.	M. F. Braña, A. Gradillas, A. Gómez, N. Acero, F. Llinares, D. Muñoz-Mingarrro, C. Abradelo, F. Rey-Stolle, M. Yuste, J. Campos, M. Á. Gallo, A. Espinosa, J. Med. Chem. 2004, 47, 2236-2242.
13.	S. M. Sondhi, R. Rani, P. Roy, S. K. Agrawal, A. K. Saxena, Bioorg. Med. Chem. Lett. 2009, 19, 1534-1538.
14.	L. Deng, Y. J. Hu, J. Het. Chem. 2007, 44, 597-601.
15.	M. Gul, N. Ocal, Can. J. Chem. 2010, 88, 323-330.
16.	D. Birney, K. Lim Tang, J. H. P. Koh, B. R. Pool, J. M. White, J. Am. Chem. Soc. 2002, 124, 5091-5099.
17.	Y. W. Goh, B. R. Pool, J. M. White, J. Org. Chem. 2008, 73, 151-156.
18.	G. Goksu, N. Ocal, D. E. Kaufmann, Molecules 2010, 15, 1302-1308.
Povzetek
Opisana je [3+2] cikloadicija N-metilnih derivatov nesubstituiranih imidov z različnimi nitril oksidi, pri čemer nastanejo novi premosteni izoksazolinski derivati, ki so potencialno biološki aktivni.